2,4-disubstituted pyrimidine derivative salt, polymorph, preparation method, pharmaceutical composition, and use

Abstract

The present invention relates to a 2,4-disubstituted pyrimidine derivative salt, a polymorph, a preparation method, a pharmaceutical composition, and the use. The structure of the 2,4-disubstituted pyrimidine derivative salt is represented by formula (1), and the polymorph thereof is polymorph I, polymorph II, polymorph III, polymorph IV, polymorph V, polymorph VI, polymorph VII or polymorph VIII. The present invention provides a variety of polymorphs, having the advantages of high selectivity, good activity, and low toxic side effects, etc., of the compound of formula (1). The polymorphs have excellent characteristics such as high purity, good solubility, stable physical and chemical properties, resistance to high temperature, high humidity, and intense light or low hygroscopicity.

Description

Salts, crystal forms, preparation methods, pharmaceutical compositions and uses of 2,4-disubstituted pyrimidine derivatives

[0001] This application claims priority to Chinese patent application 2025101144164, filed on January 24, 2025. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to a 2,4-disubstituted pyrimidine derivative salt, its crystal form, preparation method, pharmaceutical composition, and uses. Background Technology

[0003] Myeloproliferative neoplasms (MPNs) are a group of malignant myeloproliferative disorders originating from pluripotent hematopoietic stem cells. They are characterized by excessive proliferation of one or more myeloid cell lineages, leading to an increase in one or more lineages in the peripheral blood. These disorders tend to cause thrombosis, extramedullary hematopoiesis, myelofibrosis, and transformation into acute leukemia. These diseases include polycythemia vera (PV), primary thrombocytosis (PT), and primary myelofibrosis (PMF).

[0004] Current clinical treatments cannot cure myelofibrosis (MPNs). Recent studies have found that JAK2 kinase, a member of the Janus kinase (JAK) family, plays a crucial role in MPNs. The JAK-signal transducer and transcription activator (JAK-STAT) pathway controls the survival, proliferation, and differentiation of various cells through cytokine-mediated signal transduction. JAK2 phosphorylation, downstream STAT phosphorylation, and activation of gene transcription ultimately lead to increased proliferation, differentiation, and survival of erythrocytes and myeloid cells. Several JAK2 inhibitors are currently undergoing clinical trials. Among them, the JAK2 inhibitor Ruxolitinib has been approved by the FDA for myelofibrosis, while others such as Lestaurtinib (CEP701), CYT-387, LY2784544, and BMS-911543 are still in clinical research.

[0005] Furthermore, recent research indicates that FMS-like tyrosine kinase 3 (FLT3) mutations are also closely related to MPNs: knocking in FLT3 with an ITD (internal tandem repeat) mutation in mice can lead to myeloproliferative disorders. FLT3 is a receptor tyrosine kinase that plays a crucial role in the development of hematopoietic progenitor cells. Approximately 30% of patients with acute myeloid leukemia (AML) have activated FLT3 internal tandem repeat (ITD) mutations, a high-risk factor for disease relapse. Small molecule FLT3 inhibitors have been tested in clinical trials as single agents or in combination with chemotherapy; however, to date, these candidates have either failed to produce sufficient initial response or maintain therapeutic efficacy, primarily due to secondary resistance. Clinical data also show a sharp decline in peripheral blood leukemia cells after treatment, but with little bone marrow response. One possible mechanism for this failure is the existence of independent alternative survival pathways through which leukemia cells can adapt via further genetic mutations or metabolic adaptations. These pathways may include mTOR-PI3K-Akt, JAK-STAT, or Ras-MAPK. Simultaneously inhibiting these pathways may free leukemia cells from FLT3 restriction.

[0006] Building on this, simultaneously targeting the JAK2 pathway offers several advantages: (a) JAK2 mutations are rarely found in AML cases; (b) elevated phosphorylated JAK2 levels are observed in AML; and (c) in the FLT3-ITD strain, the negative regulators of JAK signaling, namely the inhibitors of cytokines 1 / 2 / 3, are significantly downregulated. Furthermore, there is evidence that inhibiting both the JAK2 and FLT3 signaling pathways can enhance clinical efficacy in AML patients with FLT3-ITD mutations. Based on this, JAK2 / FLT3 dual-target inhibitors for treating myelofibrosis are gradually becoming a research hotspot. Currently, the JAK2 / FLT3 dual-target inhibitor Fedratinib has been approved by the FDA for priority use in myelofibrosis, and the macrocyclic compound Pacritinib is also undergoing phase III clinical trials (for the treatment of myelofibrosis). However, existing JAK2 / FLT3 dual-target inhibitors have poor enzyme activity and low oral bioavailability, which still cannot meet medical needs. Therefore, developing inhibitors with better selectivity, higher activity, and better in vivo pharmacokinetic properties is currently a hot research topic. Summary of the Invention

[0007] This invention provides a 2,4-disubstituted pyrimidine derivative salt, crystal form, preparation method, pharmaceutical composition, and use.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] In a first aspect, the present invention provides a crystal form of a 2,4-disubstituted pyrimidine derivative salt, which is crystal form I of the compound of formula (1), crystal form II of the compound of formula (1), crystal form III of the monohydrate of the compound of formula (1), crystal form IV of the compound of formula (1), crystal form V of the monohydrate of the compound of formula (1), crystal form VI of the dihydrate of the compound of formula (1), crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1), or crystal form VIII of the N,N-dimethylformamide solvate of the compound of formula (1).

[0010] In the N-methylpyrrolidone solvate of the compound of formula (1), the molar ratio of the compound of formula (1) to N-methylpyrrolidone is 1:0.5;

[0011] In the N,N-dimethylformamide solvate of the compound of formula (1), the molar ratio of the compound of formula (1) to N,N-dimethylformamide is 1:1;

[0012] The crystal form I of the compound of formula (1) has diffraction peaks at 6.78±0.20°, 21.01±0.20° and 26.22±0.20° in its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0013] Crystal form II of the compound of formula (1) has diffraction peaks at 18.11±0.20°, 18.40±0.20° and 21.67±0.20° in its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0014] The monohydrate of the compound of formula (1) has crystal form III, and its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 6.68±0.20°, 21.90±0.20° and 25.28±0.20°.

[0015] The crystal form IV of the compound of formula (1) has diffraction peaks at 18.13±0.20°, 19.86±0.20° and 24.36±0.20° in its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0016] The crystal form V of the monohydrate of the compound of formula (1) has diffraction peaks at 6.89±0.20°, 18.73±0.20° and 25.70±0.20° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0017] The crystal form VI of the dihydrate of the compound of formula (1) has diffraction peaks at 16.16±0.20°, 19.76±0.20° and 20.14±0.20° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0018] The crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1) has diffraction peaks at 6.57±0.20°, 9.87±0.20° and 26.56±0.20° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0019] The crystal form VIII of the N,N-dimethylformamide solvate of the compound of formula (1) has diffraction peaks at 6.37±0.20°, 9.56±0.20° and 22.46±0.20° in its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0020] In this invention, the crystal form I of the compound of formula (1) may have diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern expressed as 2θ angle using Cu-Kα radiation: 3.38±0.20°, 9.71±0.20°, 10.18±0.20°, 12.14±0.20°, 13.58±0.20°, 14.19±0.20°, 15.82±0.20°, 16.31±0.20°, 17.03±0.20°, 17.30±0.20°, 1 7.62±0.20°, 18.58±0.20°, 18.76±0.20°, 19.50±0.20°, 20.34±0.20°, 21.54±0.20°, 22.07±0.20°, 23.05±0.20°, 23.48±0.20°, 27.40±0.20°, 28.56±0.20°, 30.65±0.20°, 31.80±0.20°, 32.62±0.20° and 37.81±0.20°.

[0021] Preferably, the crystal form I of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 6.78±0.20°, 17.30±0.20°, 18.76±0.20°, 21.01±0.20° and 26.22±0.20°.

[0022] More preferably, the crystal form I of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.78±0.20°, 10.18±0.20°, 12.14±0.20°, 16.31±0.20°, 17.03±0.20°, 17.30±0.20°, 18.58±0.20°, 18.76±0.20°, 21.01±0.20°, 23.05±0.20°, 23.48±0.20° and 26.22±0.20°.

[0023] In some embodiments of the invention, the crystal form I of the compound of formula (1), whose X-ray powder diffraction pattern, expressed as 2θ angle, is obtained using Cu-Kα radiation, is at 3.377°, 6.778°, 9.707°, 10.182°, 12.142°, 13.577°, 14.193°, 15.818°, 16.307°, 17.027°, 17.297°, 17 Diffraction peaks are observed at 0.619°, 18.577°, 18.763°, 19.497°, 20.341°, 21.013°, 21.544°, 22.069°, 23.054°, 23.478°, 26.220°, 27.403°, 28.560°, 30.647°, 31.799°, 32.618°, and 37.808°.

[0024] In one aspect of the present invention, the crystal form I of the compound of formula (1) has a diffraction peak and relative intensity as shown in Table 3 when X-ray powder diffraction pattern is expressed in terms of Cu-Kα radiation and 2θ angle.

[0025] In one aspect of the present invention, the crystal form I of the compound of formula (1) has an X-ray powder diffraction pattern, which is basically shown in Figure 1, using Cu-Kα radiation and expressed in 2θ angle.

[0026] In this invention, the thermogravimetric analysis curve of crystal form I of the compound of formula (1) shows a weight loss of 0.73% at room temperature to 120.0±3℃.

[0027] In one aspect of the present invention, the thermogravimetric analysis curve of crystal form I of the compound of formula (1) is basically as shown in Figure 2.

[0028] In this invention, the differential scanning spectroscopy curve of crystal form I of the compound of formula (1) has an endothermic peak starting point at 135.8±3℃. Further, the endothermic peak reaches its peak value at 140.2±3℃. Even further, the enthalpy change between 135.8±3℃ and 140.2±3℃ is 33.61 J / g.

[0029] In one aspect of the present invention, the differential scanning quantization curve of crystal form I of the compound of formula (1) is basically as shown in Figure 2.

[0030] In this invention, the crystal form II of the compound of formula (1), when subjected to Cu-Kα radiation and expressed at an angle of 2θ, may also exhibit diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern: 6.92±0.20°, 7.76±0.20°, 9.53±0.20°, 10.76±0.20°, 11.25±0.20°, 13.26±0.20°, 13.90±0.20°, 14.46±0.20°, 14.78±0.20°, 18.58±0.20°, 18.80±0.20°, 20.02±0. 0.20°, 20.72±0.20°, 21.11±0.20°, 22.63±0.20°, 23.44±0.20°, 24.02±0.20°, 24.32±0.20°, 25.00±0.20°, 25.69±0.20°, 27.42±0.20°, 27.91±0.20°, 28.43±0.20°, 29.15±0.20°, 30.32±0.20°, 31.43±0.20°, 33.44±0.20° and 36.31±0.20°.

[0031] Preferably, the crystal form II of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 13.26±0.20°, 18.11±0.20°, 18.40±0.20°, 21.67±0.20° and 23.44±0.20°.

[0032] More preferably, the crystal form II of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 9.53±0.20°, 13.26±0.20°, 13.90±0.20°, 18.11±0.20°, 18.40±0.20°, 21.67±0.20°, 23.44±0.20° and 27.91±0.20°.

[0033] In some embodiments of the invention, the crystal form II of the compound of formula (1), whose X-ray powder diffraction pattern, expressed as 2θ angle, is obtained using Cu-Kα radiation, is at 6.920°, 7.763°, 9.527°, 10.756°, 11.251°, 13.256°, 13.896°, 14.457°, 14.778°, 18.114°, 18.404°, 18.582°, and 18.800°. Diffraction peaks are observed at 20.019°, 20.722°, 21.110°, 21.669°, 22.625°, 23.435°, 24.019°, 24.322°, 25.002°, 25.691°, 27.424°, 27.909°, 28.431°, 29.150°, 30.317°, 31.435°, 33.444°, and 36.312°.

[0034] In one aspect of the present invention, the crystal form II of the compound of formula (1) has a Cu-Kα radiation X-ray powder diffraction pattern expressed in 2θ angle with diffraction peaks and relative intensities as shown in Table 6.

[0035] In one aspect of the present invention, the crystal form II of the compound of formula (1) has an X-ray powder diffraction pattern, which is basically shown in Figure 3, using Cu-Kα radiation and expressed at an angle of 2θ.

[0036] In this invention, the thermogravimetric analysis curve of crystal form II of the compound of formula (1) shows a weight loss of 1.18% at room temperature to 100±3℃.

[0037] In one aspect of the present invention, the thermogravimetric analysis curve of crystal form II of the compound of formula (1) is basically as shown in Figure 4.

[0038] In this invention, the differential scanning spectroscopy curve of crystal form II of the compound of formula (1) has an endothermic peak starting point at 149.2±3℃. Further, the endothermic peak reaches its peak value at 152.4±3℃. Even further, the enthalpy change between 149.2±3℃ and 152.4±3℃ is 48.92 J / g.

[0039] In one aspect of the present invention, the differential scanning quantization curve of crystal form II of the compound of formula (1) is basically as shown in Figure 4.

[0040] In one embodiment of the present invention, the crystal form III of the monohydrate of the compound of formula (1) has diffraction peaks at 6.68±0.20°, 21.90±0.20° and 25.38±0.20° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0041] In this invention, the crystal form III of the monohydrate of compound (1) may also exhibit diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ: 3.34±0.20°, 9.35±0.20°, 10.01±0.20°, 12.01±0.20°, 13.01±0.20°, 13.36±0.20°, 14.37±0.20°, 15.56±0.20°, 16.24±0.20°, 16.87±0.20°, 17.26±0.20°, 17.80±0.20°, 18.33±0.20°, 18.5 7±0.20°, 19.38±0.20°, 20.53±0.20°, 21.11±0.20°, 22.39±0.20°, 23.52±0.20°, 24.37±0.20°, 24.85±0.20°, 26.30±0.20°, 26.90±0.20°, 27.62±0.20°, 28.84±0.20°, 29.76±0.20°, 30.38±0.20°, 31.00±0.20°, 31.88±0.20°, 33.89±0.20°, 36.79±0.20° and 39.06±0.20°.

[0042] Preferably, the crystal form III of the monohydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 6.68±0.20°, 9.35±0.20°, 16.24±0.20°, 19.38±0.20°, 21.90±0.20° and 25.38±0.20°.

[0043] More preferably, the crystal form III of the monohydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 3.34±0.20°, 6.68±0.20°, 9.35±0.20°, 12.01±0.20°, 14.37±0.20°, 16.24±0.20°, 19.38±0.20°, 21.90±0.20°, 24.85±0.20°, 25.38±0.20° and 27.62±0.20°.

[0044] In some embodiments of the invention, the crystal form III of the monohydrate of the compound of formula (1) is shown by X-ray powder diffraction using Cu-Kα radiation, expressed in 2θ angles at 3.343°, 6.677°, 9.352°, 10.014°, 12.013°, 13.008°, 13.359°, 14.370°, 15.557°, 16.242°, 16.867°, 17.262°, 17.798°, 18.334°, 18. Diffraction peaks are present at 569°, 19.376°, 20.531°, 21.109°, 21.898°, 22.389°, 23.522°, 24.370°, 24.845°, 25.377°, 26.300°, 26.897°, 27.620°, 28.840°, 29.764°, 30.378°, 31.002°, 31.884°, 33.891°, 36.790°, and 39.064°.

[0045] In one embodiment of the present invention, the crystal form III of the monohydrate of the compound of formula (1) has a diffraction peak and relative intensity as shown in Table 9 using Cu-Kα radiation and X-ray powder diffraction pattern expressed in 2θ angle.

[0046] In one aspect of the present invention, the crystal form III of the compound monohydrate of formula (1) is shown in Figure 5 by using Cu-Kα radiation and X-ray powder diffraction pattern expressed in 2θ angle.

[0047] In this invention, the thermogravimetric analysis curve of the monohydrate of the compound of formula (1) in crystal form III shows a weight loss of up to 2.89% at room temperature to 100±3℃.

[0048] In one aspect of the present invention, the thermogravimetric analysis curve of crystal form III of the compound monohydrate of formula (1) is basically as shown in Figure 6.

[0049] In this invention, the differential scanning spectroscopy curve of crystal form III of the monohydrate of compound (1) has an endothermic peak starting point at 136.4±3℃. Further, the endothermic peak reaches its peak value at 138.5±3℃. Even further, the enthalpy change between 136.4±3℃ and 138.5±3℃ is 20.97 J / g.

[0050] In one aspect of the present invention, the differential scanning quantization curve of crystal form III of the compound monohydrate of formula (1) is basically as shown in Figure 6.

[0051] In one aspect of the present invention, the crystal form III of the monohydrate of the compound of formula (1) is the crystal form of the monohydrate or channel hydrate formed after the compound of formula (1) absorbs water molecules.

[0052] In this invention, the crystal form IV of the compound of formula (1), when subjected to Cu-Kα radiation and expressed at an angle of 2θ, may also exhibit diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern: 6.58±0.20°, 9.03±0.20°, 10.23±0.20°, 11.33±0.20°, 12.87±0.20°, 15.79±0.20°, 15.97±0.20°, 16.14±0.20°, 16.69±0.20°, 18.71±0.20°, 19.24± 0.20°, 19.86±0.20°, 23.86±0.20°, 24.18±0.20°, 24.69±0.20°, 25.04±0.20°, 25.47±0.20°, 27.04±0.20°, 27.37±0.20°, 27.85±0.20°, 29.29±0.20°, 31.06±0.20°, 31.38±0.20°, 32.75±0.20°, 33.42±0.20° and 34.43±0.20°.

[0053] Preferably, the crystal form IV of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 6.58±0.20°, 12.87±0.20°, 18.13±0.20°, 19.24±0.20°, 19.86±0.20°, 24.36±0.20° and 25.04±0.20°.

[0054] More preferably, the crystal form IV of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.58±0.20°, 12.87±0.20°, 16.14±0.20°, 16.69±0.20°, 18.13±0.20°, 19.24±0.20°, 19.86±0.20°, 24.18±0.20°, 24.36±0.20°, 25.04±0.20° and 25.47±0.20°.

[0055] In some embodiments of the invention, the crystal form IV of the compound of formula (1), whose X-ray powder diffraction pattern, expressed as 2θ angle, using Cu-Kα radiation, is at 6.578°, 9.031°, 10.233°, 11.334°, 12.871°, 15.788°, 15.967°, 16.137°, 16.693°, 18.125°, 18.709°, and 19.23°, is described. Diffraction peaks are present at 6°, 19.533°, 19.861°, 23.861°, 24.177°, 24.359°, 24.688°, 25.043°, 25.472°, 27.039°, 27.369°, 27.845°, 29.286°, 31.064°, 31.384°, 32.751°, 33.417°, and 34.434°.

[0056] In one aspect of the present invention, the crystal form IV of the compound of formula (1) has a diffraction peak and relative intensity as shown in Table 11, which is obtained by using Cu-Kα radiation and X-ray powder diffraction pattern expressed in 2θ angle.

[0057] In one aspect of the present invention, the crystal form IV of the compound of formula (1) has an X-ray powder diffraction pattern, which is basically shown in Figure 7, using Cu-Kα radiation and expressed in 2θ angle.

[0058] In this invention, the thermogravimetric analysis curve of crystal form IV of the compound of formula (1) shows a weight loss of up to 0.51% at room temperature to 100±3℃.

[0059] In one aspect of the present invention, the thermogravimetric analysis curve of crystal form IV of the compound of formula (1) is basically as shown in Figure 8.

[0060] In this invention, the differential scanning calorimetry curve of crystal form IV of the compound of formula (1) has an endothermic peak starting point at 134.7±3℃. Further, the endothermic peak reaches its peak value at 137.9±3℃. Even further, the enthalpy change between 134.7±3℃ and 137.9±3℃ is 62.44 J / g.

[0061] In one aspect of the present invention, the differential scan curve of crystal form IV of the compound of formula (1) is basically as shown in Figure 8.

[0062] In this invention, the crystal form V of the monohydrate of the compound of formula (1) may have diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ: 3.42±0.20°, 9.32±0.20°, 10.33±0.20°, 12.07±0.20°, 13.81±0.20°, 14.07±0.20°, and 15.74±0.20°. 16.52±0.20°, 17.33±0.20°, 18.07±0.20°, 19.07±0.20°, 19.81±0.20°, 20.93±0.20°, 21.75±0.20°, 22.29±0.20°, 23.10±0.20°, 24.51±0.20°, 26.70±0.20° and 31.86±0.20°.

[0063] Preferably, the crystal form V of the monohydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 3.42±0.20°, 6.89±0.20°, 10.33±0.20°, 16.52±0.20°, 18.73±0.20° and 25.70±0.20°.

[0064] More preferably, the crystal form V of the monohydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 3.42±0.20°, 6.89±0.20°, 10.33±0.20°, 16.52±0.20°, 18.73±0.20°, 19.07±0.20°, 20.93±0.20°, 21.75±0.20° and 25.70±0.20°.

[0065] In some embodiments of the present invention, the crystal form V of the monohydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 3.420°, 6.892°, 9.317°, 10.325°, 12.066°, 13.805°, 14.065°, 15.743°, 16.523°, 17.333°, 18.066°, 18.727°, 19.071°, 19.806°, 20.934°, 21.747°, 22.293°, 23.095°, 24.513°, 25.699°, 26.695°, and 31.857°.

[0066] In one embodiment of the present invention, the crystal form V of the monohydrate of the compound of formula (1) has a diffraction peak and relative intensity as shown in Table 13 when X-ray powder diffraction pattern is expressed in terms of Cu-Kα radiation and 2θ angle.

[0067] In one aspect of the present invention, the crystal form V of the monohydrate of the compound of formula (1) is shown in Figure 9 as an X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ.

[0068] In this invention, the thermogravimetric analysis curve of crystal form V of the compound monohydrate of formula (1) shows a weight loss of up to 3.14% at room temperature to 100±3℃.

[0069] In one aspect of the present invention, the thermogravimetric analysis curve of crystal form V of the hydrate of compound (1) is basically as shown in Figure 10.

[0070] In this invention, the differential scanning spectroscopy curve of crystal form V of the monohydrate of compound (1) has an endothermic peak starting point at 35.6±3℃. Further, the endothermic peak reaches its peak value at 38.6±3℃. Even further, the enthalpy change between 35.6±3℃ and 38.6±3℃ is 114.5 J / g.

[0071] In this invention, the differential scanning spectroscopy curve of crystal form V of the monohydrate of compound (1) has an endothermic peak starting point at 135.7±3℃. Further, the endothermic peak reaches its peak value at 139.5±3℃. Even further, the enthalpy change between 135.7±3℃ and 139.5±3℃ is 28.58 J / g.

[0072] In one aspect of the present invention, the differential scanning quantization curve of the crystal form V of the hydrate of the compound of formula (1) is basically as shown in Figure 10.

[0073] In one aspect of the present invention, the crystal form V of the monohydrate of the compound of formula (1) is the crystal form of the monohydrate or channel hydrate formed after the compound of formula (1) absorbs water molecules.

[0074] In this invention, the crystal form VI of the dihydrate of the compound of formula (1) may have diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle: 5.01±0.20°, 8.60±0.20°, 10.02±0.20°, 10.35±0.20°, 10.81±0.20°, 11.00±0.20°, 12.78±0.20°, 13. 37±0.20°, 13.84±0.20°, 14.59±0.20°, 16.66±0.20°, 17.33±0.20°, 17.52±0.20°, 18.06±0.20°, 18.38±0.20°, 19.17±0.20°, 19.47±0.20°, 19.95±0.20°, 21.26±0.20°, 21.71±0.20° °, 22.62±0.20°, 23.06±0.20°, 23.43±0.20°, 23.71±0.20°, 23.96±0.20°, 24.40±0.20°, 24.73±0.20°, 25.51±0.20°, 25.72±0.20°, 26.96±0.20°, 27.44±0.20°, 28.44±0.20°, 29.01 ±0.20°, 30.06±0.20°, 30.32±0.20°, 30.86±0.20°, 31.43±0.20°, 32.09±0.20°, 32.72±0.20°, 33.46±0.20°, 34.50±0.20°, 36.37±0.20°, 37.47±0.20°, 37.87±0.20° and 38.66±0.20°.

[0075] Preferably, the crystal form VI of the dihydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 16.16±0.20°, 19.76±0.20°, 20.14±0.20°, 21.26±0.20° and 26.96±0.20°.

[0076] More preferably, the crystal form VI of the dihydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 10.02±0.20°, 16.16±0.20°, 19.76±0.20°, 19.95±0.20°, 20.14±0.20°, 21.26±0.20°, 23.71±0.20°, 24.73±0.20°, 25.72±0.20° and 26.96±0.20°.

[0077] In some embodiments of the invention, the crystal form VI of the dihydrate of the compound of formula (1) is shown by X-ray powder diffraction using Cu-Kα radiation, expressed in 2θ angles at 5.006°, 8.595°, 10.018°, 10.353°, 10.806°, 10.996°, 12.778°, 13.371°, 13.843°, 14.590°, 16.155°, 16.656°, 17.330°, 17.519°, 18.064°, 18.384°, 19.172°, 19.474°, 19.755°, 19.946°, and 20. Diffraction peaks are present at 143°, 21.259°, 21.714°, 22.622°, 23.058°, 23.431°, 23.706°, 23.962°, 24.399°, 24.732°, 25.509°, 25.720°, 26.958°, 27.441°, 28.435°, 29.005°, 30.057°, 30.323°, 30.858°, 31.432°, 32.724°, 33.458°, 34.501°, 36.373°, 37.468°, 37.867°, and 38.661°.

[0078] In one embodiment of the present invention, the crystal form VI of the dihydrate of the compound of formula (1) has a diffraction pattern of X-ray powder diffraction using Cu-Kα radiation and expressed in terms of 2θ angle, which has diffraction peaks and relative intensities as shown in Table 15.

[0079] In one aspect of the present invention, the crystal form VI of the dihydrate of the compound of formula (1) is shown in Figure 11 as an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle.

[0080] In this invention, the thermogravimetric analysis curve of crystal form VI of the dihydrate of the compound of formula (1) shows a weight loss of up to 6.45% at room temperature to 100±3℃.

[0081] In one aspect of the present invention, the thermogravimetric analysis curve of crystal form VI of the dihydrate of compound (1) is basically as shown in Figure 12.

[0082] In this invention, the differential scanning spectroscopy curve of crystal form VI of the dihydrate of formula (1) has an endothermic peak starting point at 66.3±3℃. Further, the endothermic peak reaches its peak value at 76.6±3℃. Even further, the enthalpy change between 66.3±3℃ and 76.6±3℃ is 76.97 J / g.

[0083] In this invention, the differential scanning calorimetry curve of crystal form VI of the dihydrate of the compound of formula (1) can have an endothermic peak at 137.1±3℃.

[0084] In one aspect of the present invention, the differential scan curve of crystal form VI of the dihydrate of compound (1) is basically as shown in Figure 12.

[0085] In one aspect of the present invention, the crystal form VI of the dihydrate of the compound of formula (1) is the crystal form of the dihydrate or channel hydrate formed after the compound of formula (1) absorbs water molecules.

[0086] In this invention, the crystal form VII of the N-methylpyrrolidone solvate of formula (1) may have diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern expressed as 2θ angle using Cu-Kα radiation: 3.28±0.20°, 8.96±0.20°, 11.37±0.20°, 13.65±0.20°, 15.65±0.20°, 16.12±0.20°, 16.95±0.20°, 18.46±0.20°, 18.81±0.20°, 19.49±0.20°, 20.14±0.20°. 20.99±0.20°, 21.55±0.20°, 21.93±0.20°, 23.17±0.20°, 24.20±0.20°, 24.55±0.20°, 25.02±0.20°, 25.43±0.20°, 26.29±0.20°, 27.36±0.20°, 27.70±0.20°, 28.34±0.20°, 30.66±0.20°, 31.68±0.20°, 35.06±0.20°, 36.89±0.20° and 39.16±0.20°.

[0087] Preferably, the crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1) has diffraction peaks at 6.57±0.20°, 9.87±0.20°, 18.46±0.20°, 23.17±0.20° and 26.56±0.20° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

[0088] In some embodiments of the present invention, the crystal form VII of the N-methylpyrrolidone solvate of compound (1) is obtained by X-ray powder diffraction using Cu-Kα radiation, expressed as 2θ angles at 3.277°, 6.570°, 8.962°, 9.868°, 11.367°, 13.654°, 15.650°, 16.120°, 16.950°, 18.462°, 18.810°, and 19.491°. Diffraction peaks are observed at 20.137°, 20.994°, 21.548°, 21.930°, 23.173°, 24.196°, 24.549°, 25.020°, 25.427°, 26.288°, 26.557°, 27.362°, 27.696°, 28.342°, 30.655°, 31.683°, 35.055°, 36.887°, and 39.162°.

[0089] In one embodiment of the present invention, the crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1) has a diffraction peak and relative intensity as shown in Table 18 using Cu-Kα radiation and X-ray powder diffraction pattern expressed in 2θ angle.

[0090] In one aspect of the present invention, the crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1) is shown in Figure 13 as an X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ.

[0091] In this invention, the thermogravimetric analysis curve of crystal form VII of the N-methylpyrrolidone solvate of formula (1) shows a weight loss of up to 1.42% at room temperature to 100±3℃.

[0092] In one aspect of the present invention, the thermogravimetric analysis curve of crystal form VII of the N-methylpyrrolidone solvate of formula (1) is basically as shown in Figure 14.

[0093] In this invention, the differential scanning spectroscopy curve of crystal form VII of the N-methylpyrrolidone solvate of formula (1) has an endothermic peak starting point at 110.0±3℃. Further, the endothermic peak reaches its peak value at 114.1±3℃. Even further, the enthalpy change between 110.0±3℃ and 114.1±3℃ is 44.44 J / g.

[0094] In one aspect of the present invention, the differential scan curve of crystal form VII of the N-methylpyrrolidone solvate of formula (1) is basically as shown in Figure 14.

[0095] In one aspect of the present invention, the NMR spectrum of the crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1) is basically as shown in Figure 15.

[0096] In one aspect of the present invention, the crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1) is the crystal form of the solvate or the channel solvate formed by the absorption of N-methylpyrrolidone by the compound of formula (1).

[0097] In this invention, the crystal form VIII of the N,N-dimethylformamide solvate of formula (1) may also exhibit diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ: 3.18±0.20°, 6.67±0.20°, 9.12±0.20°, 10.01±0.20°, 10.43±0.20°, 11.80±0.20°, 12.46±0.20°, 16.15±0.20°, 16.32±0.20°, 16.85±0.20°, and 17.72±0.20°. 18.26±0.20°, 18.72±0.20°, 19.20±0.20°, 19.43±0.20°, 20.55±0.20°, 20.84±0.20°, 23.45±0.20°, 24.65±0.20°, 24.96±0.20°, 25.70±0.20°, 26.56±0.20°, 27.98±0.20°, 28.68±0.20°, 29.02±0.20°, 29.66±0.20°, 32.69±0.20°, and 35.62±0.20°.

[0098] Preferably, the crystal form VIII of the N,N-dimethylformamide solvate of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.37±0.20°, 9.56±0.20°, 16.15±0.20°, 19.20±0.20°, 22.46±0.20°, and 24.96±0.20°.

[0099] More preferably, the crystal form VIII of the N,N-dimethylformamide solvate of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.37±0.20°, 9.56±0.20°, 16.15±0.20°, 17.72±0.20°, 19.20±0.20°, 20.84±0.20°, 22.46±0.20°, 24.96±0.20°, 25.70±0.20° and 29.02±0.20°.

[0100] In some embodiments of the present invention, the crystal form VIII of the N,N-dimethylformamide solvate of compound (1) has an X-ray powder diffraction pattern, expressed as a 2θ angle, under Cu-Kα radiation at 3.177°, 6.367°, 6.671°, 9.121°, 9.562°, 10.013°, 10.425°, 11.798°, 12.458°, 16.146°, 16.325°, and 16.854°. Diffraction peaks are observed at 17.718°, 18.262°, 18.720°, 19.202°, ​​19.428°, 20.545°, 20.843°, 22.460°, 23.448°, 24.649°, 24.960°, 25.698°, 26.556°, 27.980°, 28.675°, 29.016°, 29.658°, 32.688°, and 35.615°.

[0101] In one embodiment of the present invention, the crystal form VIII of the N,N-dimethylformamide solvate of the compound of formula (1) has a Cu-Kα radiation X-ray powder diffraction pattern in terms of 2θ angles with diffraction peaks and relative intensities as shown in Table 21.

[0102] In one aspect of the present invention, the crystal form VIII of the N,N-dimethylformamide solvate of the compound of formula (1) is shown in Figure 16 as an X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ.

[0103] In this invention, the thermogravimetric analysis curve of crystal form VIII of the N,N-dimethylformamide solvate of formula (1) shows a weight loss of up to 6.09% at room temperature to 100±3℃.

[0104] In one aspect of the present invention, the thermogravimetric analysis curve of crystal form VIII of the N,N-dimethylformamide solvate of formula (1) is basically as shown in Figure 17.

[0105] In this invention, the differential scanning spectroscopy curve of crystal form VIII of the N,N-dimethylformamide solvate of formula (1) has an endothermic peak starting point at 116.1±3℃. Further, the endothermic peak reaches its peak value at 118.5±3℃. Even further, the enthalpy change between 116.1±3℃ and 118.5±3℃ is 10.01 J / g.

[0106] In one aspect of the present invention, the differential scan curve of crystal form VIII of the N,N-dimethylformamide solvate of formula (1) is basically as shown in Figure 17.

[0107] In one aspect of the present invention, the NMR spectrum of crystal form VIII of the N,N-dimethylformamide solvate of formula (1) is basically as shown in Figure 18.

[0108] In one aspect of the present invention, the crystal form VIII of the N,N-dimethylformamide solvate of the compound of formula (1) is the crystal form of the solvate or the channel solvate formed by the absorption of N,N-dimethylformamide by the compound of formula (1).

[0109] In a second aspect, the present invention provides a method for preparing the crystal form of the 2,4-disubstituted pyrimidine derivative salt as described above, which is any one of the following methods one to eight;

[0110] When the crystal form is crystal form I of the compound of formula (1), the method is method one, which includes the following steps: gas-solid diffusion of the compound of formula (1) in a solvent atmosphere, wherein the solvent is ethanol, isopropanol, acetone, acetonitrile, dichloromethane, methyl tert-butyl ether or water, and when the solvent is water, the relative humidity of the solvent atmosphere is 50%RH-75%RH.

[0111] Preferably, the ambient temperature for the gas-solid diffusion is 20-30°C;

[0112] Preferably, the gas-solid diffusion time is 6-8 days, for example, 7 days;

[0113] Preferably, after the gas-solid diffusion, drying is performed. The drying time can be 2-4 hours, for example, 3 hours. The drying temperature can be 20-30°C.

[0114] When the crystal form is crystal form II of the compound of formula (1), the method is method two, which includes the following steps: stirring the suspension containing the compound of formula (1) at 40-60°C, wherein the solvent of the suspension is isopropanol, isopropyl acetate, methyl tert-butyl ether, toluene, a mixture of isopropanol and water or a mixture of 2-methyltetrahydrofuran and water;

[0115] Preferably, in the suspension, the ratio of the compound of formula (1) to the solvent is 1 g: (10-40) mL;

[0116] Preferably, the stirring temperature is 50°C;

[0117] Preferably, the stirring time is 3-7 days;

[0118] In some embodiments of the present invention, the solvent is a mixture of isopropanol and water, wherein the volume ratio of isopropanol to water is (40-50):1, for example 49:1, and the amount ratio of the compound of formula (1) to the solvent in the suspension is, for example, 1g:(10-20)mL.

[0119] In some embodiments of the present invention, the solvent is 2-methyltetrahydrofuran and water, and the volume ratio of 2-methyltetrahydrofuran to water is (40-50):1, for example 49:1. In the suspension, the ratio of the amount of the compound of formula (1) to the amount of the solvent is, for example, 1g:(10-20)mL.

[0120] Preferably, after stirring, the solid is separated and dried; the drying temperature can be 20-30℃; the drying time can be 2-4 hours.

[0121] When the crystal form is crystal form III of the compound of formula (1), the method is method three, which includes the following steps: gas-liquid diffusion of a clear liquid containing the compound of formula (1) in an atmosphere of antisolvent, wherein the good solvent of the clear liquid is methanol, ethanol, water, N-methylpyrrolidone or N,N-dimethylformamide; and the antisolvent is isopropanol, ethyl acetate, isopropyl acetate, acetone, acetonitrile, methyl tert-butyl ether or methyl ethyl ketone;

[0122] Preferably, when the good solvent is methanol, the concentration of the compound of formula (1) in the clarified liquid is 50-100 mg / mL;

[0123] Preferably, when the good solvent is ethanol, the concentration of the compound of formula (1) in the clarified liquid is 5-15 mg / mL;

[0124] Preferably, when the good solvent is ethanol, the antisolvent is ethyl acetate, isopropyl acetate, or methyl tert-butyl ether;

[0125] Preferably, after the gas-liquid diffusion, drying is performed. The drying time can be 2-4 hours; the drying temperature can be 20-30°C.

[0126] When the crystal form is crystal form IV of the compound of formula (1), the method is method four, which includes the following steps: stirring the suspension containing the compound of formula (1) at 20-30°C, wherein the solvent of the suspension is isopropanol;

[0127] Preferably, in the suspension, the ratio of the compound of formula (1) to the solvent is 1 g: (10-40) mL;

[0128] Preferably, the stirring time is 3-7 days;

[0129] Preferably, after stirring, the solid is separated and then dried. The drying temperature can be 20-30°C; the drying time can be 2-4 hours.

[0130] When the crystal form is crystal form V of the compound of formula (1), the method is method five, which includes the following steps: stirring the suspension containing the compound of formula (1) at 20-30°C, wherein the solvent of the suspension is 2-methyltetrahydrofuran and water;

[0131] Preferably, the volume ratio of the 2-methyltetrahydrofuran to the water is (40-50):1, for example, 49:1;

[0132] Preferably, in the suspension, the ratio of the compound of formula (1) to the solvent is 1 g: (10-40) mL;

[0133] Preferably, the stirring time is 3-7 days;

[0134] Preferably, after stirring, the solid is separated and dried; the drying temperature can be 20-30℃. The drying time can be 2-4 hours.

[0135] When the crystal form is crystal form VI of the compound of formula (1), the method is method six, which includes the following steps: gas-solid diffusion of the compound of formula (1) in an atmosphere with a relative humidity of 80%RH-95%RH.

[0136] Preferably, the gas-solid diffusion is carried out in an atmosphere with a relative humidity of 92.5% RH;

[0137] Preferably, the gas-solid diffusion time is 6-8 days, for example, 7 days;

[0138] Preferably, after the gas-solid diffusion, drying is performed; the drying time can be 2-4 hours, for example 3 hours. The drying temperature can be 20-30°C.

[0139] When the crystal form is crystal form VII of the compound of formula (1), the method is method seven, which includes the following steps: adding an antisolvent to a clear liquid containing the compound of formula (1) and then stirring; the good solvent of the clear liquid is N-methylpyrrolidone; the antisolvent is isopropyl acetate, methyl tert-butyl ether or toluene;

[0140] Preferably, the concentration of the compound of formula (1) in the clarified liquid is 50-100 mg / mL;

[0141] Preferably, the volume ratio of the good solvent to the antisolvent is 1:(4-10);

[0142] In one aspect of the present invention, the antisolvent is isopropyl acetate, and the volume ratio of the good solvent to the antisolvent is 1:10.

[0143] In one aspect of the present invention, the antisolvent is methyl tert-butyl ether, and the volume ratio of the good solvent to the antisolvent is 1:4;

[0144] In one aspect of the present invention, the antisolvent is toluene, and the volume ratio of the good solvent to the antisolvent is 1:10;

[0145] Preferably, the stirring time is 15-20 hours, for example, 18 hours;

[0146] Preferably, after stirring, the solid is separated and then dried. The drying temperature can be 20-30°C, and the drying time can be 2-4 hours.

[0147] When the crystal form is crystal form VIII of the compound of formula (1), the method is method eight, which includes the following steps: adding the clear liquid containing the compound of formula (1) to the antisolvent, and then stirring; the good solvent of the clear liquid is N,N-dimethylformamide; the antisolvent is toluene;

[0148] Preferably, the concentration of the compound of formula (1) in the clarified liquid is 50-100 mg / mL;

[0149] Preferably, the volume ratio of the good solvent to the antisolvent is 1:(9-10);

[0150] Preferably, the stirring time is 15-20 hours, for example, 18 hours;

[0151] Preferably, after stirring, the solid is separated and then dried. The drying temperature can be 20-30°C; the drying time can be 2-4 hours.

[0152] In some embodiments, the compound of formula (1) is the crystal form obtained in Example 111 of patent CN114423750A. In this invention, it is named crystal form M.

[0153] In some embodiments, the compound of formula (1) is prepared by the following method: compound 1f is dissolved in an organic solvent by heating, maleic acid is added, dissolved, cooled to precipitate, filtered, and the compound of formula (1) is obtained.

[0154] The maleic acid is in the form of solid maleic acid or a solution of maleic acid in an organic solvent;

[0155] The organic solvent is ethyl acetate, ethanol, or a combination thereof;

[0156] In some embodiments, the molar ratio of compound 1f to maleic acid is 1:(1-2).

[0157] In some embodiments, the molar ratio of compound 1f to maleic acid is 1:(1-1.8).

[0158] In some embodiments, the molar ratio of compound 1f to maleic acid is 1:1 or 1:1.6.

[0159] Thirdly, the present invention provides a pharmaceutical composition comprising the crystal form of a 2,4-disubstituted pyrimidine derivative salt as described above.

[0160] Preferably, the pharmaceutical composition further includes a first filler. The first filler is preferably selected from one or more of microcrystalline cellulose, lactose, and pregelatinized starch. The mass ratio of the first filler to the crystal form of the 2,4-disubstituted pyrimidine derivative salt is preferably (25-45):25.

[0161] Preferably, the pharmaceutical composition further includes a second filler. The second filler is preferably selected from one or more of microcrystalline cellulose, lactose, and pregelatinized starch. The mass ratio of the second filler to the crystal form of the 2,4-disubstituted pyrimidine derivative salt is preferably (25-45):25.

[0162] Preferably, the pharmaceutical composition further includes a flow aid. The flow aid is preferably colloidal silica. The preferred mass ratio of the flow aid to the crystal form of the 2,4-disubstituted pyrimidine derivative salt is (1-3):25.

[0163] Preferably, the pharmaceutical composition further includes a disintegrant. The disintegrant is preferably selected from one or more of croscarmellose sodium, croscarmellose, croscarmellose calcium, and carboxymethyl starch sodium. The mass ratio of the disintegrant to the crystal form of the 2,4-disubstituted pyrimidine derivative salt is preferably (1-3):25.

[0164] Preferably, the pharmaceutical composition further includes a lubricant. The lubricant is preferably selected from one or more of magnesium stearate, stearic acid, sodium stearate fumarate, sodium docusate, and calcium stearate. The mass ratio of the lubricant to the crystal form of the 2,4-disubstituted pyrimidine derivative salt is preferably (1-3):25.

[0165] Preferably, the pharmaceutical composition comprises the following parts by weight: 25 parts of the crystalline form of the 2,4-disubstituted pyrimidine derivative salt, 25 parts of the first filler, 45 parts of the second filler, 1 part of the lubricant, 1 part of the flow aid, and 3 parts of the disintegrant. The first filler is preferably pregelatinized starch. The second filler is preferably microcrystalline cellulose. The flow aid is preferably colloidal silica. The disintegrant is preferably crospovidone. The lubricant is preferably magnesium stearate. In this invention, the dosage form of the pharmaceutical composition may be tablets, capsules, powders, granules, ointments, solutions, suspensions, injections, inhalers, gels, microspheres, or aerosols.

[0166] Fourthly, the present invention provides the use of the crystal form of the 2,4-disubstituted pyrimidine derivative salt as described above or the pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing immune diseases, inflammatory-related diseases or tumors.

[0167] In this invention, the tumor can be a solid tumor and / or a hematologic malignancy. The solid tumor can be lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, ovarian cancer, breast cancer, prostate cancer, bladder cancer, kidney cancer, esophageal cancer, cervical cancer, pancreatic cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, thyroid cancer, brain cancer, lymphoma, epidermal hyperplasia, psoriasis, or prostate cancer. The hematologic malignancy can be acute myeloid leukemia, chronic myeloid leukemia, myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, myelodysplastic syndrome, myelodysplastic syndrome, myelofibrosis, multiple myeloma, polycythemia vera, or spinal sarcoma.

[0168] In this invention, the immune diseases mentioned can be psoriasis, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, etc.), Sjögren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, vertebral arthritis, polymyositis, dermatomyositis (DM), periarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, Addison's disease, abnormal immune response, arthritis, dermatitis, radiation dermatitis, etc. Especially psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis, or systemic lupus erythematosus.

[0169] In this invention, the inflammation-related diseases may include inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome (SIRS), postoperative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngitis, gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary embolism, scleropulmonary disease, or pulmonary sarcoidosis.

[0170] Preferably, it is used to prepare a drug having at least one of the following uses:

[0171] Prepare JAK2 inhibitors or FLT3 inhibitors;

[0172] Treatment and / or prevention of acute myeloid leukemia;

[0173] Treatment and / or prevention of myelodysplastic syndromes;

[0174] Treatment and / or prevention of myelofibrosis;

[0175] Treatment and / or prevention of essential thrombocytosis;

[0176] Treatment and / or prevention of polycythemia vera;

[0177] Treatment and / or prevention of graft-versus-host disease.

[0178] The terms "good solvent" and "bad solvent" in this invention are relative. In a pair of solvents, the one with higher solubility is a good solvent, and the one with lower solubility is a bad solvent.

[0179] The X-ray powder diffraction or DSC pattern and TGA pattern disclosed in this invention, which are substantially the same, also fall within the scope of this invention.

[0180] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0181] As used in this invention, "crystal of the present invention", "crystal form of the present invention", "crystal form of the present invention" and the like are interchangeable.

[0182] The "room temperature" mentioned in this invention generally refers to 25±5℃.

[0183] The crystal structure of the present invention can be analyzed using various analytical techniques known to those skilled in the art, including but not limited to X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).

[0184] The X-ray powder diffraction pattern testing parameters for each crystal form in this invention were obtained using Cu-Kα radiation.

[0185] The "2θ or 2θ angle" mentioned in this invention refers to the peak position, expressed in degrees (°), set in an X-ray diffraction experiment and typically in the horizontal coordinate unit of a diffraction pattern. If the incident beam is diffracted when it forms an angle θ with a lattice plane, the experimental setup requires recording the reflected beam at a 2θ angle. It should be understood that a specific 2θ value for a particular crystal form mentioned herein means a 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein, and the error range of the 2θ can be ±0.3, ±0.2, or ±0.1.

[0186] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0187] The reagents and raw materials used in this invention are all commercially available.

[0188] The positive and progressive effects of the present invention are as follows: The present invention provides a variety of crystal forms of the compound of formula (1) with advantages such as high selectivity, good activity and low toxicity. The crystal form has excellent properties such as high purity, good solubility, stable physical and chemical properties, resistance to high temperature, high humidity and strong light or low hygroscopicity. Attached Figure Description

[0189] Figure 1 shows the X-ray powder diffraction pattern of crystal form I of compound (1).

[0190] Figure 2 shows the DSC and TGA spectra of crystal form I of compound (1).

[0191] Figure 3 shows the X-ray powder diffraction pattern of crystal form II of compound (1).

[0192] Figure 4 shows the DSC and TGA spectra of crystal form II of compound (1).

[0193] Figure 5 shows the X-ray powder diffraction pattern of crystal form III of compound (1).

[0194] Figure 6 shows the DSC and TGA spectra of crystal form III of compound (1).

[0195] Figure 7 shows the X-ray powder diffraction pattern of crystal form IV of compound (1).

[0196] Figure 8 shows the DSC and TGA spectra of crystal form IV of compound (1).

[0197] Figure 9 shows the X-ray powder diffraction pattern of crystal form V of compound (1).

[0198] Figure 10 shows the DSC and TGA spectra of crystal form V of compound (1).

[0199] Figure 11 shows the X-ray powder diffraction pattern of crystal form VI of compound (1).

[0200] Figure 12 shows the DSC and TGA spectra of crystal form VI of compound (1).

[0201] Figure 13 shows the X-ray powder diffraction pattern of crystal form VII of compound (1).

[0202] Figure 14 shows the DSC and TGA spectra of crystal form VII of compound (1).

[0203] Figure 15 shows the NMR spectrum of crystal form VII of compound (1).

[0204] Figure 16 shows the X-ray powder diffraction pattern of crystal form VIII of compound (1).

[0205] Figure 17 shows the DSC and TGA spectra of crystal form VIII of compound (1).

[0206] Figure 18 shows the NMR spectrum of crystal form VIII of compound (1).

[0207] Figure 19 shows the amorphous X-ray powder diffraction pattern of the compound of formula (1).

[0208] Figure 20 shows the dynamic water adsorption curve (DVS) of crystal form II of compound (1), where 1 represents one adsorption cycle and 2 represents one desorption cycle.

[0209] Figure 21 shows the dynamic water adsorption curve (DVS) of crystal form IV of compound (1), where 1 represents one adsorption cycle and 2 represents one desorption cycle.

[0210] Figure 22 shows the dynamic water adsorption curve (DVS) of the amorphous compound of formula (1), where 1 represents one adsorption cycle and 2 represents one desorption cycle. Detailed Implementation

[0211] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the concept and scope of the invention.

[0212] It is understood that the numerical values ​​described and protected in this invention are approximate. Variations within these values ​​may be attributed to equipment calibration, equipment errors, crystal purity, crystal size, sample size, and other factors.

[0213] It is understood that the crystal forms of the present invention are not limited to those that are exactly the same as the characteristic spectra described in the accompanying drawings, such as XRPD, DSC, and TGA. Any crystal form having a characteristic spectra that are substantially the same or essentially the same as those spectra described in the accompanying drawings falls within the scope of the present invention.

[0214] It is understood that, as is well known in the field of differential scanning calorimetry (DSC), the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compounds of the present invention have DSC plots with characteristic peak positions that have substantially the same properties as the DSC plots provided in the accompanying drawings of the present invention, with a measurement error tolerance of ±5°C, generally required to be ±3°C.

[0215] The present invention relates to an X-ray powder diffractometer (XRPD) method.

[0216] Testing instrument: Rigaku SmartLab SE.

[0217] Radiation source: Cu-Kα radiation.

[0218] Detection conditions: X-ray tube voltage 40kV, X-ray tube current 40mA, scanning range 3-40° (2θ), step size 0.02°, scanning speed 5° / min.

[0219] Testing basis: Appendix IX, X-ray powder diffraction method, of the Pharmacopoeia of the People's Republic of China (2010 Edition, Part II).

[0220] This invention relates to a differential scanning calorimeter (DSC) method.

[0221] Testing instrument: Netzsch STA 449 F3

[0222] Detection conditions: Nitrogen gas, 50 mL / min

[0223] Scanning program: 30-400℃, heating rate: 10℃ / min

[0224] Sample weight tested: ~3mg (alumina sample dish)

[0225] Testing standard: JY / T 014-1996 General Rules for Thermal Analysis

[0226] Thermogravimetric Analysis (TGA) method of this invention

[0227] Testing instrument: Netzsch STA 449 F3

[0228] Detection conditions: Nitrogen gas, 50 mL / min

[0229] Scanning program: 30-400℃, heating rate: 10℃ / min

[0230] Sample weight tested: ~5mg (alumina sample dish)

[0231] Testing standard: JY / T 014-1996 General Rules for Thermal Analysis

[0232] This invention involves nuclear magnetic resonance spectroscopy analysis ( 1 H-NMR method

[0233] Testing instrument: Nuclear magnetic resonance spectrometer (JMTC-400 / 54 / JJ / YH)

[0234] Detection conditions: 400MHz, deuterated DMSO solution.

[0235] Example 1

[0236] The synthesis route is as follows:

[0237] The specific steps are as follows:

[0238] Compound 1f (0.75 kg, 1.6 mol) was stirred in ethyl acetate (12 L) and heated to reflux until dissolved (in other examples, ethanol (12 L) can be used). The preparation method of compound 1f is the same as that in Example 44 of patent CN 114423750 A. Maleic acid (186 g, 1.6 mol) solid was added (in other examples, an ethyl acetate / anhydrous ethanol solution of maleic acid (3 L / 300 ml) or an ethanol solution of maleic acid (3 L) can be used), stirred, and then cooled to an internal temperature of 50-55 °C. After filtration, the filter cake was dried to obtain compound 1 (compound of formula (1)) crystal form M.

[0239] m / z: 468.28783 [M+H] + .

[0240] 1H NMR (400MHz, DMSO-d6) δ9.44(s,1H),8.34(s,1H),8.29(s,1H),8.10(s,1H),7.81(dd,J=15.5,2.4 Hz,1H),7.51-7.44(m,1H),7.03(dd,J=10.1,8.8Hz,1H),6.06(s,2H),5.40(s,1H),4.64(hept,J= 6.6Hz,1H),3.78(t,J=5.2Hz,2H),3.44-3.32(m,3H),3.30-3.10(br,2H),2.81(s,3H),2.75-2.65 (m, 2H), 2.32 (s, 3H), 2.09 (d, J = 11.6Hz, 2H), 1.84 (qd, J = 11.7, 3.8Hz, 2H), 1.49 (d, J = 11.6Hz, 6H).

[0241] Nuclear magnetic resonance (NMR) data confirmed that the molar ratio of compound 1f to maleic acid in the salt obtained by the above preparation method was 1:1.

[0242] Subsequent studies have found that this crystal form is an unstable transitional crystal form, which is not conducive to the development of subsequent formulations, etc. Based on this crystal form, this invention further studies more promising crystal forms.

[0243] In the following examples, a total of 8 crystalline forms and 1 amorphous form of the compound of formula (1) are provided, namely: crystalline form I (amorphous), crystalline form II (amorphous), crystalline form III (monohydrate), crystalline form IV (amorphous), crystalline form V (monohydrate), crystalline form VI (dihydrate), crystalline form VII (N-methylpyrrolidone solvate), crystalline form VIII (N,N-dimethylformamide solvate) and amorphous form, as detailed in Table 1 below:

[0244] Table 1

[0245] Example 2: Preparation of crystal form I of compound (1)

[0246] Preparation method: gas-solid diffusion. Approximately 20 mg of compound (1) was weighed into a sample vial. The solid sample was placed in an environment containing different solvents and subjected to gas-solid diffusion at room temperature (approximately 25°C). After 7 days, the sample was dried at room temperature for 3 hours to obtain crystal form I of compound (1). The experimental data are shown in Table 2 below:

[0247] Table 2

[0248] The XRPD pattern of crystal form I is shown in Figure 1, and the analytical data are shown in Table 3 below:

[0249] Table 3

[0250] The DSC and TGA spectra of crystal form I are shown in Figure 2, and the analytical data are shown in Table 4 below:

[0251] Table 4

[0252] The TGA of crystal form I showed a weight loss of only 0.73% in the range of room temperature to 120°C, which is extremely small and indicates that it is a non-crystalline form. Secondly, combined with the TGA curve, the compound directly decomposes and loses weight at around 173°C, and there is no water of crystallization in the molecular structure, which also indicates that it is a non-crystalline form.

[0253] Example 3: Preparation of crystal form II of compound (1)

[0254] Preparation method: 50℃ suspension and slurry preparation. Weigh approximately 50 mg of the compound sample of formula (1) into a sample vial, add 0.5 mL (in other examples, any value between 0.5-2 mL) of different solvents to prepare a suspension, then stir at 50℃ for 3 days (in other examples, 7 days), remove the supernatant by centrifugation, and vacuum dry at room temperature for 4 hours to obtain crystal form II of the compound of formula (1). The experimental results are shown in Table 5 below:

[0255] Table 5

[0256] The XRPD pattern of crystal form II is shown in Figure 3, and the analytical data are shown in Table 6 below:

[0257] Table 6

[0258] The DSC and TGA spectra of crystal form II are shown in Figure 4, and the analytical data are shown in Table 7 below:

[0259] Table 7

[0260] The TGA of crystal form II showed a weight loss of only 1.18% in the range of room temperature to 100°C, which is extremely small and indicates that it is an amorphous form. Secondly, based on the TGA curve, the compound began to decompose and lose weight at around 168°C, and there was no water of crystallization in the molecular structure, which also indicates that it is an amorphous form.

[0261] Example 4: Preparation of crystal form III of compound (1)

[0262] Preparation method: gas-liquid diffusion. Based on the results of the preliminary solubility test, methanol, ethanol, water, N-methylpyrrolidone, and N,N-dimethylformamide were selected as good solvents for the gas-liquid diffusion experiment. Approximately 30 mg of the compound sample of formula (1) was weighed and dissolved in the corresponding good solvent (stirring at room temperature). After filtration, the filtrate was placed in a sample bottle and then placed in an environment containing different antisolvents for gas-liquid diffusion. The solid sample was collected and dried under vacuum at room temperature for ~4 hours, which is the crystal form III of the compound of formula (1). The experimental results are shown in Table 8 below:

[0263] Table 8

[0264] The XRPD pattern of crystal form III is shown in Figure 5, and the analytical data are shown in Table 9 below:

[0265] Table 9

[0266] The DSC and TGA spectra of crystal form III are shown in Figure 6, and the analytical data are shown in Table 10 below:

[0267] Table 10

[0268] Based on the weight loss and water content of crystal form III, and by converting the molar ratio according to the molecular weight, the water loss is 2.89%, the molar amount is 1.62 mmol, and the compound content is 1.66 mmol. The molar ratio of the two is approximately 1:1, so the water content is 1 water molecule.

[0269] According to the TGA curve, water loss is slow within the 100℃ range, and no obvious step similar to the loss of water of crystallization is observed. Furthermore, no change in melting point due to water loss is found in the DSC curve, proving that the water content is not water of crystallization. Since neither adsorbed water nor pipe water is water of crystallization, it is classified as non-crystalline hygroscopic or pipe hydrate.

[0270] Example 5: Preparation of crystal form IV of compound (1)

[0271] Preparation method: Room temperature suspension and slurry preparation. Weigh about 50 mg of the compound sample of formula (1) into a sample bottle, add 0.5 mL (in other examples, it can be any value between 0.5-2 mL, i.e., the ratio of g / mL = 1:(10-40)) of isopropanol to prepare a suspension, then stir at room temperature for 3 days (in other examples, it can be 7 days), remove the supernatant by centrifugation, and dry under vacuum at room temperature for 4 hours to obtain the solid, i.e., crystal form IV of the compound of formula (1).

[0272] The XRPD pattern of crystal form IV is shown in Figure 7, and the analytical data are shown in Table 11 below:

[0273] Table 11

[0274] The DSC and TGA spectra of crystal form IV are shown in Figure 8, and the analytical data are shown in Table 12 below:

[0275] Table 12

[0276] The TGA of crystal form IV showed a weight loss of only 0.51% in the range of room temperature to 100°C, which is extremely small and indicates that it is an amorphous form. Secondly, combined with the TGA curve, the compound began to decompose and lose weight at 166°C, and there was no water of crystallization in the molecular structure, which also indicates that it is an amorphous form.

[0277] Example 6: Preparation of crystal form V of compound (1)

[0278] Preparation method: The mixture was suspended and slurried at room temperature. Approximately 50 mg of the compound sample of formula (1) was weighed into a sample vial, and 0.5 mL (in other examples, any value between 0.5 and 2 mL, i.e., a volume ratio of g / mL = 1:(10-40)) of a mixture of 2-methyltetrahydrofuran and water was added (V). 2-甲基四氢呋喃 / V 水 =49:1), prepare a suspension, then stir at room temperature for 3 days (or 7 days in other embodiments), remove the supernatant by centrifugation, and obtain a solid after vacuum drying at room temperature for 4 hours, namely the crystal form V of the compound of formula (1).

[0279] The XRPD pattern of crystal form V is shown in Figure 9, and the analytical data are shown in Table 13 below:

[0280] Table 13

[0281] The DSC and TGA spectra of crystal form V are shown in Figure 10, and the analytical data are shown in Table 14 below:

[0282] Table 14

[0283] Based on the weight loss water content of crystal form V, and combined with the molecular weight to calculate the molar ratio, the molar amount of 3.14% water loss is 1.74 mmol, and the compound content is 1.66 mmol. The molar ratio of the two is approximately 1:1, so the water content is 1 water molecule.

[0284] Example 7: Preparation of crystal form VI of compound (1)

[0285] Preparation method: gas-solid diffusion. Weigh about 20 mg of compound (1) sample into a sample bottle, place the solid sample in an environment of 92.5% RH for gas-solid diffusion, take the sample after 7 days and directly perform XRPD test (without drying), and dry at room temperature for 3 hours before XRPD test, and the crystal form VI of compound (1) was obtained in both cases.

[0286] The XRPD pattern of crystal form VI is shown in Figure 11, and the analytical data are shown in Table 15 below:

[0287] Table 15

[0288] The DSC and TGA spectra of crystal form VI are shown in Figure 12, and the analytical data are shown in Table 16 below:

[0289] Table 16

[0290] Based on the weight loss water content of crystal form VI, and combined with the molecular weight to calculate the molar ratio, the molar amount of 6.45% water loss is 3.58 mmol, and the compound content is 1.60 mmol. The molar ratio of the two is approximately 2:1, so the water content is 2 water molecules.

[0291] Example 8: Preparation of crystal form VII of compound (1)

[0292] Preparation method: forward dissolution. Weigh approximately 40 mg of the compound sample of formula (1) and add it to the corresponding good solvent to dissolve it completely (stirring at room temperature). Then filter it and add the antisolvent to the filtrate until a solid precipitates, or add up to ten times the volume of antisolvent. Keep stirring for about 18 hours. Collect the sample by filtration and dry it under vacuum at room temperature for 4 hours, which is the crystal form VII of the compound of formula (1). The experimental results are shown in Table 17 below:

[0293] Table 17

[0294] The XRPD pattern of crystal form VII is shown in Figure 13, and the analytical data are shown in Table 18 below:

[0295] Table 18

[0296] The DSC and TGA spectra of crystal form VII are shown in Figure 14, and the analytical data are shown in Table 19 below:

[0297] Table 19

[0298] The NMR spectrum of crystal form VII is shown in Figure 15. Based on the HNMR of crystal form VII, the solvent is determined to be N-methylpyrrolidone. Furthermore, the molar ratio calculated based on the molecular weight is approximately 1:0.5, therefore the solvent molecule content is 0.5.

[0299] Example 9: Preparation of crystal form VIII of compound (1)

[0300] Preparation method: Reverse dissolution. Weigh approximately 30 mg of the compound sample of formula (1) and add it to the corresponding good solvent to dissolve it completely (stirring at room temperature). Then filter it and quickly pour the filtrate into a sample bottle containing 10 times its volume of reverse solvent. Keep stirring for about 18 hours. Collect the sample by centrifugation and dry it under vacuum at room temperature for 4 hours to obtain the crystal form VIII of the compound of formula (1). The experimental results are shown in Table 20 below:

[0301] Table 20

[0302] The XRPD pattern of crystal form VIII is shown in Figure 16, and the analytical data are shown in Table 21 below:

[0303] Table 21

[0304] The DSC and TGA spectra of crystal form VIII are shown in Figure 17, and the analytical data are shown in Table 22 below:

[0305] Table 22

[0306] The NMR spectrum of crystal form VIII is shown in Figure 18. Based on the HNMR, the solvent is N,N-dimethylformamide, and the molar ratio is approximately 1:1 based on the molecular weight, therefore the solvent molecule content is 1.

[0307] Example 10: Preparation of the amorphous form of compound (1)

[0308] Preparation method: Amorphous samples can be obtained by freeze drying. Weigh 500 mg of the compound sample of formula (1), dissolve it in 5 mL of water, freeze dry the solution to obtain the amorphous compound of formula (1), and its X-ray powder diffraction pattern is shown in Figure 19.

[0309] Example 1: Dynamic water adsorption curve (DVS) analysis of different crystal forms of compound (1)

[0310] 1. Test method: The moisture absorption weight gain of compound (1) crystal form II, crystal form IV and amorphous form under different humidity conditions was investigated using a dynamic moisture adsorption instrument (DVS INTRINSIC). The humidity program was 0%RH, 95%RH, 0%RH, and the gradient was 10%RH.

[0311] 2. Test results: The DVS test data for crystal form II is shown in Figure 20, the DVS test data for crystal form IV is shown in Figure 21, and the DVS test data for amorphous crystals is shown in Figure 22.

[0312] Test results show that both crystal form II and crystal form IV are slightly hygroscopic, and both meet the development characteristics of the formulation. The test results are shown in Table 23 below:

[0313] Table 23

[0314] Example 2: Solubility test of different crystal forms of compound (1)

[0315] 1. Test Method: The solubility of the compound of formula (1) in crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, and amorphous samples was tested. 30 mg of each sample was placed in a sample vial, and then 3 mL of biological media (FaSSIF, FeSSIF, and FaSSGF) and water were added respectively. All suspensions were shaken at 200 rpm at 37°C. Samples were taken and observed at 0.5, 2, and 24 hours, and the solubility of the filtrate was tested. In addition, XRPD tests were performed on the remaining solid sample and filtrate after 24 hours.

[0316] 2. Test Results: The results showed that crystal forms I, II, III, IV, V, and VI, as well as the amorphous sample, exhibited good solubility in FaSSIF, FaSSGF, and water. Solids were visibly dissolved within 0.5 hours, indicating a solubility greater than 10 mg / mL, thus classifying the compound as a highly soluble drug. All samples showed oil formation after shaking in FaSSIF for 0.5 hours. After 24 hours of shaking, no solids remained in any sample; therefore, XRPD testing was not performed. Specific experimental results are shown in Table 24 below.

[0317] Table 24

[0318] Example 3: Stability test of different crystal forms of compound (1)

[0319] 1. Test Method: The stability of different crystal forms and amorphous samples of compound (1) was investigated. 30 mg of crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI and amorphous sample were placed at 60℃ (closed) and 25℃ / 92.5% RH (open) for 10 days respectively. The chemical stability of the solid samples after placement was analyzed by HPLC.

[0320] 2. Test Results: Under high temperature conditions: amorphous and crystalline forms V and VI showed slight degradation and instability, while other crystalline forms were relatively stable; under high humidity conditions: all forms were relatively stable. Overall, except for amorphous, crystalline forms V and VI, the chemical stability of other crystalline forms was good and could meet the requirements for formulation development. The test results are shown in Table 25 below.

[0321] Table 25

[0322] The long-term stability of crystal form I of compound (1) was further investigated under two conditions: condition one was 40℃±2℃ / 75%, RH±5%RH, for 6 months; condition two was 25℃±2℃, 60%RH±5%RH, for 24 months. The results showed that crystal form I had good crystal form and chemical stability. The experimental results are shown in Table 26 below.

[0323] Table 26

[0324] Example 4: Pharmacokinetic evaluation of free alkaline compounds and crystal form I in SD rats

[0325] 1. Test method: Accurately weigh the compound of formula (1f) and the crystal form I of the compound of formula (1). Add DMSO to dissolve the compound into a solution of 50 mg / ml, and then use sodium chloride solution for injection to prepare a solution of 0.75 mg / ml for administration.

[0326] 21 male rats, at 7.5 mg / kg -1 After oral administration, approximately 0.03 mL of blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 48 h post-administration. The blood samples were centrifuged at 3500 rpm for 15 min, and the supernatant plasma was collected. 5 μL of plasma was transferred to an EP tube, and 100 μL of a solution containing 20 ng / mL was added. -1 Proteins were precipitated with acetonitrile containing the internal standard SAHA, vortexed for 30 seconds, centrifuged at 13000 rpm for 15 minutes, and the supernatant was collected and injected into sample vials for analysis. Standard curve range: 1-3000 ng / ml - 1 .

[0327] 2. Test Results: The experimental data are shown in the table below. Compared with the free alkali compound, crystal form I is better absorbed in vivo. Crystal form I has good pharmacokinetic properties in rats, including good oral bioavailability, exposure, half-life, and clearance, as detailed in Table 27 below.

[0328] Table 27

[0329] Example 5: Compressibility of tablets made from different crystal forms of the compound of formula (1)

[0330] 1. Granulation and tableting of the formulation: 25 parts by weight of different crystal forms of the compound of formula (1) (crystal form I, II, III, IV, V or VI) are mixed with pregelatinized starch (25 parts by weight), microcrystalline cellulose (45 parts by weight), magnesium stearate (1 part by weight), colloidal silica (1 part by weight), and crospovidone (3 parts by weight), granulated, and then tableted. Among them, the pregelatinized starch was purchased from COLORCON, model STARCH1500; the microcrystalline cellulose was purchased from JRS Pharma GmbH&Co.KG, model PH102; the colloidal silica was purchased from Cabot Rheinfleden GmbH, model M5P; and the crospovidone was purchased from ISP Chemical LLC, model XL-10.

[0331] 2. The results show that the compressibility of crystal forms I, II and IV is significantly better than that of crystal forms III, V and VI, as detailed in Table 28 below.

[0332] Table 28

[0333] Example 6: Pharmacokinetic evaluation of different crystal forms of compound (1) in beagle dogs

[0334] 1. Canine PK test: The formulations of the compound of formula (1) in crystal form I, II, III, IV, V and crystal form VI were prepared according to the effect example 5 and tableted and administered once to evaluate the pharmacokinetic behavior in male and female beagle dogs.

[0335] Beagles were divided into 6 groups of 6 animals each, with half males and half females. Each group was given a single oral dose of 25 mg of crystal form I, II, III, IV, V, and VI tablets. Plasma samples were collected from each group before (0) and at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration. The concentrations of compound (1) in the plasma samples were determined using liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0336] 2. Results show that the systemic exposure (AUC) of compound crystal forms I, II, and IV in formula (1) 0-last and C max All were relatively high, with systemic exposures (AUC) of crystal forms III, V, and VI being particularly high. 0-last and C max The pharmacokinetic parameters of the combined male and female dogs were assessed as shown in Table 29 below.

[0337] Table 29

[0338] In summary, the crystal forms of the present invention have good solubility, superior physicochemical properties of crystal forms I, II, and IV, good compressibility in tablet preparation, and excellent pharmacokinetic characteristics.

Claims

1. A crystal form of a 2,4-disubstituted pyrimidine derivative salt, characterized in that, It is the crystal form I of the compound of formula (1), the crystal form II of the compound of formula (1), the crystal form III of the monohydrate of the compound of formula (1), the crystal form IV of the compound of formula (1), the crystal form V of the monohydrate of the compound of formula (1), the crystal form VI of the dihydrate of the compound of formula (1), the crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1), or the crystal form VIII of the N,N-dimethylformamide solvate of the compound of formula (1). In the N-methylpyrrolidone solvate of the compound of formula (1), the molar ratio of the compound of formula (1) to N-methylpyrrolidone is 1:0.5; In the N,N-dimethylformamide solvate of the compound of formula (1), the molar ratio of the compound of formula (1) to N,N-dimethylformamide is 1:1; The crystal form I of the compound of formula (1) has diffraction peaks at 6.78±0.20°, 21.01±0.20° and 26.22±0.20° in its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. Crystal form II of the compound of formula (1) has diffraction peaks at 18.11±0.20°, 18.40±0.20° and 21.67±0.20° in its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. The monohydrate of the compound of formula (1) has crystal form III, and its X-ray powder diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, has diffraction peaks at 6.68±0.20°, 21.90±0.20° and 25.38±0.20°. The crystal form IV of the compound of formula (1) has diffraction peaks at 18.13±0.20°, 19.86±0.20° and 24.36±0.20° in its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. The crystal form V of the monohydrate of the compound of formula (1) has diffraction peaks at 6.89±0.20°, 18.73±0.20° and 25.70±0.20° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. The crystal form VI of the dihydrate of the compound of formula (1) has diffraction peaks at 16.16±0.20°, 19.76±0.20° and 20.14±0.20° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. The crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1) has diffraction peaks at 6.57±0.20°, 9.87±0.20° and 26.56±0.20° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. The crystal form VIII of the N,N-dimethylformamide solvate of the compound of formula (1) has diffraction peaks at 6.37±0.20°, 9.56±0.20° and 22.46±0.20° in its X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

2. The crystalline form of the salt of a 2,4-disubstituted pyrimidine derivative according to claim 1, characterized in that, It satisfies at least one of the following conditions: (1) The crystal form I of the compound of formula (1) also has diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern expressed as 2θ angle using Cu-Kα radiation: 3.38±0.20°, 9.71±0.20°, 10.18±0.20°, 12.14±0.20°, 13.58±0.20°, 14.19±0.20°, 15.82±0.20°, 16.31±0.20°, 17.03±0.20°, 17.30±0.20°, 17 0.62±0.20°, 18.58±0.20°, 18.76±0.20°, 19.50±0.20°, 20.34±0.20°, 21.54±0.20°, 22.07±0.20°, 23.05±0.20°, 23.48±0.20°, 27.40±0.20°, 28.56±0.20°, 30.65±0.20°, 31.80±0.20°, 32.62±0.20° and 37.81±0.20°; Preferably, the crystal form I of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 6.78±0.20°, 17.30±0.20°, 18.76±0.20°, 21.01±0.20° and 26.22±0.20°; More preferably, the crystal form I of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.78±0.20°, 10.18±0.20°, 12.14±0.20°, 16.31±0.20°, 17.03±0.20°, 17.30±0.20°, 18.58±0.20°, 18.76±0.20°, 21.01±0.20°, 23.05±0.20°, 23.48±0.20° and 26.22±0.20°. For example, the crystal form I of the compound of formula (1), whose X-ray powder diffraction pattern, expressed as 2θ angle, using Cu-Kα radiation, is observed at 3.377°, 6.778°, 9.707°, 10.182°, 12.142°, 13.577°, 14.193°, 15.818°, 16.307°, 17.027°, 17.297°, and 17.619°. Diffraction peaks are observed at 18.577°, 18.763°, 19.497°, 20.341°, 21.013°, 21.544°, 22.069°, 23.054°, 23.478°, 26.220°, 27.403°, 28.560°, 30.647°, 31.799°, 32.618°, and 37.808°. (2) Crystal form II of the compound of formula (1) has a Cu-Kα radiation X-ray powder diffraction pattern expressed in 2θ angles with one or more of the following diffraction peaks: 6.92±0.20°, 7.76±0.20°, 9.53±0.20°, 10.76±0.20°, 11.25±0.20°, 13.26±0.20°, 13.90±0.20°, 14.46±0.20°, 14.78±0.20°, 18.58±0.20°, 18.80±0.20°, 20.02±0.20°. 20°, 20.72±0.20°, 21.11±0.20°, 22.63±0.20°, 23.44±0.20°, 24.02±0.20°, 24.32±0.20°, 25.00±0.20°, 25.69±0.20°, 27.42±0.20°, 27.91±0.20°, 28.43±0.20°, 29.15±0.20°, 30.32±0.20°, 31.43±0.20°, 33.44±0.20° and 36.31±0.20°; Preferably, the crystal form II of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 13.26±0.20°, 18.11±0.20°, 18.40±0.20°, 21.67±0.20° and 23.44±0.20°; More preferably, the crystal form II of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 9.53±0.20°, 13.26±0.20°, 13.90±0.20°, 18.11±0.20°, 18.40±0.20°, 21.67±0.20°, 23.44±0.20° and 27.91±0.20°. For example, crystal form II of the compound of formula (1), whose X-ray powder diffraction pattern, expressed as 2θ angle, using Cu-Kα radiation, is observed at 6.920°, 7.763°, 9.527°, 10.756°, 11.251°, 13.256°, 13.896°, 14.457°, 14.778°, 18.114°, 18.404°, 18.582°, 18.800°, and 20... Diffraction peaks are observed at 0.019°, 20.722°, 21.110°, 21.669°, 22.625°, 23.435°, 24.019°, 24.322°, 25.002°, 25.691°, 27.424°, 27.909°, 28.431°, 29.150°, 30.317°, 31.435°, 33.444°, and 36.312°. (3) The crystal form III of the monohydrate of compound (1) also exhibits diffraction peaks at one or more of the following locations in its X-ray powder diffraction pattern using Cu-Kα radiation and expressed at an angle of 2θ: 3.34±0.20°, 9.35±0.20°, 10.01±0.20°, 12.01±0.20°, 13.01±0.20°, 13.36±0.20°, 14.37±0.20°, 15.56±0.20°, 16.24±0.20°, 16.87±0.20°, 17.26±0.20°, 17.80±0.20°, 18.33±0.20°, 18.57 ±0.20°, 19.38±0.20°, 20.53±0.20°, 21.11±0.20°, 22.39±0.20°, 23.52±0.20°, 24.37±0.20°, 24.85±0.20°, 26.30±0.20°, 26.90±0.20°, 27.62±0.20°, 28.84±0.20°, 29.76±0.20°, 30.38±0.20°, 31.00±0.20°, 31.88±0.20°, 33.89±0.20°, 36.79±0.20° and 39.06±0.20°; Preferably, the crystal form III of the monohydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 6.68±0.20°, 9.35±0.20°, 16.24±0.20°, 19.38±0.20°, 21.90±0.20° and 25.38±0.20°. More preferably, the crystal form III of the monohydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 3.34±0.20°, 6.68±0.20°, 9.35±0.20°, 12.01±0.20°, 14.37±0.20°, 16.24±0.20°, 19.38±0.20°, 21.90±0.20°, 24.85±0.20°, 25.38±0.20° and 27.62±0.20°. For example, the crystal form III of the monohydrate of compound (1), with X-ray powder diffraction patterns expressed as 2θ angles using Cu-Kα radiation, is shown at 3.343°, 6.677°, 9.352°, 10.014°, 12.013°, 13.008°, 13.359°, 14.370°, 15.557°, 16.242°, 16.867°, 17.262°, 17.798°, 18.334°, 18.569°, 19.376°, Diffraction peaks are observed at 20.531°, 21.109°, 21.898°, 22.389°, 23.522°, 24.370°, 24.845°, 25.377°, 26.300°, 26.897°, 27.620°, 28.840°, 29.764°, 30.378°, 31.002°, 31.884°, 33.891°, 36.790°, and 39.064°; (4) Crystal form IV of the compound of formula (1) Its X-ray powder diffraction pattern, using Cu-Kα radiation and expressed at 2θ angles, also shows diffraction peaks at one or more of the following locations: 6.58±0.20°, 9.03±0.20°, 10.23±0.20°, 11.33±0.20°, 12.87±0.20°, 15.79±0.20°, 15.97±0.20°, 16.14±0.20°, 16.69±0.20°, 18.71±0.20°, 19.24±0.20°, 19.8 6±0.20°, 23.86±0.20°, 24.18±0.20°, 24.69±0.20°, 25.04±0.20°, 25.47±0.20°, 27.04±0.20°, 27.37±0.20°, 27.85±0.20°, 29.29±0.20°, 31.06±0.20°, 31.38±0.20°, 32.75±0.20°, 33.42±0.20° and 34.43±0.20°; Preferably, the crystal form IV of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 6.58±0.20°, 12.87±0.20°, 18.13±0.20°, 19.24±0.20°, 19.86±0.20°, 24.36±0.20° and 25.04±0.20°. More preferably, the crystal form IV of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.58±0.20°, 12.87±0.20°, 16.14±0.20°, 16.69±0.20°, 18.13±0.20°, 19.24±0.20°, 19.86±0.20°, 24.18±0.20°, 24.36±0.20°, 25.04±0.20° and 25.47±0.20°. For example, the crystal form IV of the compound of formula (1), whose X-ray powder diffraction pattern, expressed as 2θ angle, using Cu-Kα radiation, is observed at 6.578°, 9.031°, 10.233°, 11.334°, 12.871°, 15.788°, 15.967°, 16.137°, 16.693°, 18.125°, 18.709°, 19.236°, 1 Diffraction peaks are observed at 9.533°, 19.861°, 23.861°, 24.177°, 24.359°, 24.688°, 25.043°, 25.472°, 27.039°, 27.369°, 27.845°, 29.286°, 31.064°, 31.384°, 32.751°, 33.417°, and 34.434°. (5) The crystal form V of the monohydrate of the compound of formula (1) has a Cu-Kα radiation X-ray powder diffraction pattern expressed in 2θ angles, which also has diffraction peaks at one or more of the following locations: 3.42±0.20°, 9.32±0.20°, 10.33±0.20°, 12.07±0.20°, 13.81±0.20°, 14.07±0.20°, 15.74±0.20°, 16.52±0.20°, 17.33±0.20°, 18.07±0.20°, 19.07±0.20°, 19.81±0.20°, 20.93±0.20°, 21.75±0.20°, 22.29±0.20°, 23.10±0.20°, 24.51±0.20°, 26.70±0.20° and 31.86±0.20°; Preferably, the crystal form V of the monohydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 3.42±0.20°, 6.89±0.20°, 10.33±0.20°, 16.52±0.20°, 18.73±0.20° and 25.70±0.20°. More preferably, the crystal form V of the monohydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 3.42±0.20°, 6.89±0.20°, 10.33±0.20°, 16.52±0.20°, 18.73±0.20°, 19.07±0.20°, 20.93±0.20°, 21.75±0.20° and 25.70±0.20°. For example, the crystal form V of the monohydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 3.420°, 6.892°, 9.317°, 10.325°, 12.066°, 13.805°, 14.065°, 15.743°, 16.523°, 17.333°, 18.066°, 18.727°, 19.071°, 19.806°, 20.934°, 21.747°, 22.293°, 23.095°, 24.513°, 25.699°, 26.695° and 31.857°. (6) Crystal form VI of the dihydrate of compound (1) has a Cu-Kα radiation X-ray powder diffraction pattern expressed in 2θ angles, which also shows diffraction peaks at one or more of the following locations: 5.01±0.20°, 8.60±0.20°, 10.02±0.20°, 10.35±0.20°, 10.81±0.20°, 11.00±0.20°, 12.78±0.20°, 13.37± 0.20°, 13.84±0.20°, 14.59±0.20°, 16.66±0.20°, 17.33±0.20°, 17.52±0.20°, 18.06±0.20°, 18.38±0.20°, 19.17±0.20°, 19.47±0.20°, 19.95±0.20°, 21.26±0.20°, 21.71±0.20° 22.62±0.20°, 23.06±0.20°, 23.43±0.20°, 23.71±0.20°, 23.96±0.20°, 24.40±0.20°, 24.73±0.20°, 25.51±0.20°, 25.72±0.20°, 26.96±0.20°, 27.44±0.20°, 28.44±0.20°, 29.01± 0.20°, 30.06±0.20°, 30.32±0.20°, 30.86±0.20°, 31.43±0.20°, 32.09±0.20°, 32.72±0.20°, 33.46±0.20°, 34.50±0.20°, 36.37±0.20°, 37.47±0.20°, 37.87±0.20° and 38.66±0.20°; Preferably, the crystal form VI of the dihydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 16.16±0.20°, 19.76±0.20°, 20.14±0.20°, 21.26±0.20° and 26.96±0.20°; More preferably, the crystal form VI of the dihydrate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 10.02±0.20°, 16.16±0.20°, 19.76±0.20°, 19.95±0.20°, 20.14±0.20°, 21.26±0.20°, 23.71±0.20°, 24.73±0.20°, 25.72±0.20° and 26.96±0.20°. For example, the crystal form VI of the dihydrate of the compound of formula (1), with its X-ray powder diffraction pattern expressed as 2θ angle using Cu-Kα radiation, is shown at 5.006°, 8.595°, 10.018°, 10.353°, 10.806°, 10.996°, 12.778°, 13.371°, 13.843°, 14.590°, 16.155°, 16.656°, 17.330°, 17.519°, 18.064°, 18.384°, 19.172°, 19.474°, 19.755°, 19.946°, and 20.143°. Diffraction peaks are observed at 21.259°, 21.714°, 22.622°, 23.058°, 23.431°, 23.706°, 23.962°, 24.399°, 24.732°, 25.509°, 25.720°, 26.958°, 27.441°, 28.435°, 29.005°, 30.057°, 30.323°, 30.858°, 31.432°, 32.724°, 33.458°, 34.501°, 36.373°, 37.468°, 37.867°, and 38.661°. (7) The crystal form VII of the N-methylpyrrolidone solvate of formula (1) has a Cu-Kα radiation X-ray powder diffraction pattern expressed at an angle of 2θ with one or more of the following diffraction peaks: 3.28±0.20°, 8.96±0.20°, 11.37±0.20°, 13.65±0.20°, 15.65±0.20°, 16.12±0.20°, 16.95±0.20°, 18.46±0.20°, 18.81±0.20°, 19.49±0.20°, 20.14±0.20°, 2 0.99±0.20°, 21.55±0.20°, 21.93±0.20°, 23.17±0.20°, 24.20±0.20°, 24.55±0.20°, 25.02±0.20°, 25.43±0.20°, 26.29±0.20°, 27.36±0.20°, 27.70±0.20°, 28.34±0.20°, 30.66±0.20°, 31.68±0.20°, 35.06±0.20°, 36.89±0.20° and 39.16±0.20°; Preferably, the crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 6.57±0.20°, 9.87±0.20°, 18.46±0.20°, 23.17±0.20° and 26.56±0.20°. For example, the crystal form VII of the N-methylpyrrolidone solvate of formula (1), with its X-ray powder diffraction pattern expressed as 2θ angle using Cu-Kα radiation, is shown at 3.277°, 6.570°, 8.962°, 9.868°, 11.367°, 13.654°, 15.650°, 16.120°, 16.950°, 18.462°, 18.810°, 19.491°, and 20.1°. Diffraction peaks are observed at 37°, 20.994°, 21.548°, 21.930°, 23.173°, 24.196°, 24.549°, 25.020°, 25.427°, 26.288°, 26.557°, 27.362°, 27.696°, 28.342°, 30.655°, 31.683°, 35.055°, 36.887°, and 39.162°. (8) The crystal form VIII of the N,N-dimethylformamide solvate of formula (1) has a Cu-Kα radiation X-ray powder diffraction pattern, expressed as an angle of 2θ, with one or more of the following diffraction peaks: 3.18±0.20°, 6.67±0.20°, 9.12±0.20°, 10.01±0.20°, 10.43±0.20°, 11.80±0.20°, 12.46±0.20°, 16.15±0.20°, 16.32±0.20°, 16.85±0.20°, 17.72±0.20°. 18.26±0.20°, 18.72±0.20°, 19.20±0.20°, 19.43±0.20°, 20.55±0.20°, 20.84±0.20°, 23.45±0.20°, 24.65±0.20°, 24.96±0.20°, 25.70±0.20°, 26.56±0.20°, 27.98±0.20°, 28.68±0.20°, 29.02±0.20°, 29.66±0.20°, 32.69±0.20° and 35.62±0.20°; Preferably, the crystal form VIII of the N,N-dimethylformamide solvate of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation with diffraction peaks at 6.37±0.20°, 9.56±0.20°, 16.15±0.20°, 19.20±0.20°, 22.46±0.20°, and 24.96±0.20°. More preferably, the crystal form VIII of the N,N-dimethylformamide solvate of formula (1) has X-ray powder diffraction patterns expressed in 2θ angles using Cu-Kα radiation, with diffraction peaks at 6.37±0.20°, 9.56±0.20°, 16.15±0.20°, 17.72±0.20°, 19.20±0.20°, 20.84±0.20°, 22.46±0.20°, 24.96±0.20°, 25.70±0.20° and 29.02±0.20°. For example, the crystal form VIII of the N,N-dimethylformamide solvate of formula (1) has an X-ray powder diffraction pattern, expressed as 2θ angle, using Cu-Kα radiation at 3.177°, 6.367°, 6.671°, 9.121°, 9.562°, 10.013°, 10.425°, 11.798°, 12.458°, 16.146°, 16.325°, 16.854°, and 17. Diffraction peaks are observed at 718°, 18.262°, 18.720°, 19.202°, ​​19.428°, 20.545°, 20.843°, 22.460°, 23.448°, 24.649°, 24.960°, 25.698°, 26.556°, 27.980°, 28.675°, 29.016°, 29.658°, 32.688°, and 35.615°. (9) The crystal form III of the monohydrate of the compound of formula (1) is the crystal form of the monohydrate or channel hydrate formed after the compound of formula (1) absorbs water molecules. (10) The crystal form V of the monohydrate of the compound of formula (1) is the crystal form of the monohydrate or channel hydrate formed after the compound of formula (1) absorbs water molecules; (11) The crystal form VI of the dihydrate of the compound of formula (1) is the crystal form of the dihydrate or channel hydrate formed after the compound of formula (1) absorbs water molecules; (12) The crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1) is the crystal form of the solvate or the channel solvate formed by the absorption of N-methylpyrrolidone by the compound of formula (1); (13) The crystal form VIII of the N,N-dimethylformamide solvate of the compound of formula (1) is the crystal form of the solvate or the channel solvate formed by the absorption of N,N-dimethylformamide by the compound of formula (1).

3. The crystalline form of a salt of a 2,4-disubstituted pyrimidine derivative according to claim 2, characterized in that, It satisfies at least one of the following conditions: (1) The crystal form I of the compound of formula (1) has a diffraction pattern of X-ray powder diffraction using Cu-Kα radiation and expressed in 2θ angle as shown in Table 3, with diffraction peaks and relative intensities. Preferably, the crystal form I of the compound of formula (1) has an X-ray powder diffraction pattern, expressed in terms of 2θ angle, which is basically as shown in Figure 1; (2) The thermogravimetric analysis curve of crystal form I of the compound of formula (1) shows a weight loss of 0.73% at 25±5℃ to 120.0±3℃; preferably, the thermogravimetric analysis curve of crystal form I of the compound of formula (I) is basically as shown in Figure 2. (3) The differential scanning calorimetry curve of crystal form I of the compound of formula (1) has an endothermic peak at 135.8±3℃; further, it reaches the peak of the endothermic peak at 140.2±3℃; even further, the enthalpy change between 135.8±3℃ and 140.2±3℃ is 33.61J / g; for example, the differential scanning calorimetry curve of crystal form I of the compound of formula (I) is basically as shown in Figure 2; (4) The crystal form II of the compound of formula (1) has a diffraction pattern of X-ray powder diffraction using Cu-Kα radiation and expressed in 2θ angle as shown in Table 6, with diffraction peaks and relative intensities. Preferably, the crystal form II of the compound of formula (1) has an X-ray powder diffraction pattern, expressed in terms of 2θ angle, which is basically as shown in Figure 3; (5) The thermogravimetric analysis curve of crystal form II of the compound of formula (1) shows a weight loss of 1.18% at 25±5℃ to 100±3℃; preferably, the thermogravimetric analysis curve of crystal form II of the compound of formula (I) is basically as shown in Figure 4. (6) The differential scanning calorimetry curve of crystal form II of the compound of formula (1) has an endothermic peak at 149.2±3℃; further, it reaches the peak of the endothermic peak at 152.4±3℃; even further, the enthalpy change between 149.2±3℃ and 152.4±3℃ is 48.92 J / g; for example, the differential scanning calorimetry curve of crystal form II of the compound of formula (I) is basically as shown in Figure 4; (7) The crystal form III of the monohydrate of the compound of formula (1) has the diffraction peaks and relative intensities shown in Table 9 using Cu-Kα radiation and X-ray powder diffraction pattern expressed in 2θ angle. Preferably, the crystal form III of the monohydrate of the compound of formula (1) has an X-ray powder diffraction pattern, expressed in terms of 2θ angle, which is basically as shown in Figure 5. (8) The thermogravimetric analysis curve of the monohydrate of the compound of formula (1) in crystal form III shows a weight loss of 2.89% at 25±5℃ to 100±3℃; preferably, the thermogravimetric analysis curve of the monohydrate of the compound of formula (1) in crystal form III is basically as shown in Figure 6. (9) The differential scanning calorimetry curve of the monohydrate of the compound of formula (1) in crystal form III has an endothermic peak at 136.4±3℃; further, it reaches the peak of the endothermic peak at 138.5±3℃; even further, the enthalpy change between 136.4±3℃ and 138.5±3℃ is 20.97J / g; for example, the differential scanning calorimetry curve of the monohydrate of the compound of formula (1) in crystal form III is basically as shown in Figure 6; (10) The crystal form IV of the compound of formula (1) has an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle, which has the diffraction peaks and relative intensities shown in Table 11. Preferably, the crystal form IV of the compound of formula (1) has an X-ray powder diffraction pattern, expressed in terms of 2θ angle, which is basically as shown in Figure 7. (11) The thermogravimetric analysis curve of the crystal form IV of the compound of formula (1) shows a weight loss of 0.51% at 25±5℃ to 100±3℃; preferably, the thermogravimetric analysis curve of the crystal form IV of the compound of formula (1) is basically as shown in Figure 8. (12) The differential scan curve of crystal form IV of the compound of formula (1) has an endothermic peak at 134.7±3℃; further, it reaches the peak of the endothermic peak at 137.9±3℃; even further, the enthalpy change between 134.7±3℃ and 137.9±3℃ is 62.44 J / g; for example, the differential scan curve of crystal form IV of the compound of formula (1) is basically as shown in Figure 8; (13) The crystal form V of the monohydrate of the compound of formula (1) has the diffraction peaks and relative intensities shown in Table 13 as shown in Cu-Kα radiation and expressed in 2θ angle. Preferably, the crystal form V of the monohydrate of the compound of formula (1) has an X-ray powder diffraction pattern, expressed in terms of 2θ angle, which is basically as shown in Figure 9. (14) The thermogravimetric analysis curve of the crystal form V of the monohydrate of the compound of formula (1) shows a weight loss of 3.14% at 25±5℃ to 100±3℃; preferably, the thermogravimetric analysis curve of the crystal form V of the monohydrate of the compound of formula (1) is basically as shown in Figure 10. (15) The differential scanning quantization curve of crystal form V of the monohydrate of compound (1) has an endothermic peak at 35.6±3℃; further, it reaches the peak of the endothermic peak at 38.6±3℃; even further, the enthalpy change between 35.6±3℃ and 38.6±3℃ is 114.5 J / g; for example, the differential scanning quantization curve of crystal form V of the monohydrate of compound (1) is basically as shown in Figure 10; (16) The differential scanning quantization curve of crystal form V of the monohydrate of compound (1) has an endothermic peak at 135.7±3℃; further, it reaches the peak of the endothermic peak at 139.5±3℃; even further, the enthalpy change between 135.7±3℃ and 139.5±3℃ is 28.58J / g; for example, the differential scanning quantization curve of crystal form V of the monohydrate of compound (1) is basically as shown in Figure 10; (17) The crystal form VI of the dihydrate of the compound of formula (1) has the diffraction peaks and relative intensities shown in Table 15 using Cu-Kα radiation and X-ray powder diffraction pattern expressed in 2θ angle. Preferably, the crystal form VI of the dihydrate of the compound of formula (1) has an X-ray powder diffraction pattern, expressed in terms of 2θ angle, which is basically as shown in Figure 11. (18) The thermogravimetric analysis curve of crystal form VI of the dihydrate of compound (1) shows a weight loss of 6.45% at 25±5℃ to 100±3℃; preferably, the thermogravimetric analysis curve of crystal form VI of the dihydrate of compound (1) is basically as shown in Figure 12. (19) The differential scanning quantization curve of crystal form VI of the dihydrate of compound (1) has an endothermic peak at 66.3±3℃; further, it reaches the peak of the endothermic peak at 76.6±3℃; even further, the enthalpy change between 66.3±3℃ and 76.6±3℃ is 76.97J / g; for example, the differential scanning quantization curve of crystal form VI of the dihydrate of compound (1) is basically as shown in Figure 12; (20) The differential scanning quantization curve of crystal form VI of the dihydrate of compound (1) has an endothermic peak at 137.1±3℃; for example, the differential scanning quantization curve of crystal form VI of the dihydrate of compound (1) is basically as shown in Figure 12. (21) The crystal form VII of the N-methylpyrrolidone solvate of compound (1) has the following X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle, with the diffraction peaks and relative intensities shown in Table 18: Preferably, the crystal form VII of the N-methylpyrrolidone solvate of the compound of formula (1) is shown in Figure 13 as an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle; (22) The thermogravimetric analysis curve of crystal form VII of the N-methylpyrrolidone solvate of formula (1) shows a weight loss of 1.42% at 25±5℃ to 100±3℃; preferably, the thermogravimetric analysis curve of crystal form VII of the N-methylpyrrolidone solvate of formula (1) is basically as shown in Figure 14. (23) The differential scanning quantization curve of crystal form VII of the N-methylpyrrolidone solvate of formula (1) has an endothermic peak at 110.0±3℃; further, it reaches the peak of the endothermic peak at 114.1±3℃; even further, the enthalpy change between 110.0±3℃ and 114.1±3℃ is 44.44 J / g; for example, the differential scanning quantization curve of crystal form VII of the N-methylpyrrolidone solvate of formula (1) is basically as shown in Figure 14; (24) The NMR spectrum of the N-methylpyrrolidone solvate of the compound of formula (1) is basically shown in Figure 15; (25) The crystal form VIII of the N,N-dimethylformamide solvate of formula (1) has the diffraction peaks and relative intensities shown in Table 21 using Cu-Kα radiation and expressed at 2θ angle: Preferably, the crystal form VIII of the N,N-dimethylformamide solvate of the compound of formula (1) is shown in Figure 16 as an X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle. (26) The thermogravimetric analysis curve of crystal form VIII of the N,N-dimethylformamide solvate of formula (1) shows a weight loss of 6.09% at 25±5℃ to 100±3℃; preferably, the thermogravimetric analysis curve of crystal form VIII of the N,N-dimethylformamide solvate of formula (1) is basically as shown in Figure 17. (27) The differential scanning quantization curve of crystal form VIII of the N,N-dimethylformamide solvate of formula (1) has an endothermic peak at 116.1±3℃; further, it reaches the peak of the endothermic peak at 118.5±3℃; even further, the enthalpy change between 116.1±3℃ and 118.5±3℃ is 10.01J / g; for example, the differential scanning quantization curve of crystal form VIII of the N,N-dimethylformamide solvate of formula (1) is basically as shown in Figure 17; (28) The NMR spectrum of the crystal form VIII of the N,N-dimethylformamide solvate of the compound of formula (1) is basically shown in Figure 18.

4. A method for preparing the crystal form of a 2,4-disubstituted pyrimidine derivative salt as described in any one of claims 1-3, characterized in that, Any one of the following methods one through eight; When the crystal form is crystal form I of the compound of formula (1), the method is method one, which includes the following steps: gas-solid diffusion of the compound of formula (1) in a solvent atmosphere, wherein the solvent is ethanol, isopropanol, acetone, acetonitrile, dichloromethane, methyl tert-butyl ether or water, and when the solvent is water, the relative humidity of the solvent atmosphere is 50%RH-75%RH. When the crystal form is crystal form II of the compound of formula (1), the method is method two, which includes the following steps: stirring the suspension containing the compound of formula (1) at 40-60°C, wherein the solvent of the suspension is isopropanol, isopropyl acetate, methyl tert-butyl ether, toluene, a mixture of isopropanol and water or a mixture of 2-methyltetrahydrofuran and water; When the crystal form is crystal form III of the compound of formula (1), the method is method three, which includes the following steps: gas-liquid diffusion of a clear liquid containing the compound of formula (1) in an atmosphere of antisolvent, wherein the good solvent of the clear liquid is methanol, ethanol, water, N-methylpyrrolidone or N,N-dimethylformamide; and the antisolvent is isopropanol, ethyl acetate, isopropyl acetate, acetone, acetonitrile, methyl tert-butyl ether or methyl ethyl ketone; When the crystal form is crystal form IV of the compound of formula (1), the method is method four, which includes the following steps: stirring the suspension containing the compound of formula (1) at 20-30°C, wherein the solvent of the suspension is isopropanol; When the crystal form is crystal form V of the compound of formula (1), the method is method five, which includes the following steps: stirring the suspension containing the compound of formula (1) at 20-30°C, wherein the solvent of the suspension is 2-methyltetrahydrofuran and water; When the crystal form is crystal form VI of the compound of formula (1), the method is method six, which includes the following steps: The compound of formula (1) was subjected to gas-solid diffusion in an atmosphere with a relative humidity of 80%RH-95%RH; When the crystal form is crystal form VII of the compound of formula (1), the method is method seven, which includes the following steps: adding an antisolvent to a clear liquid containing the compound of formula (1) and then stirring; the good solvent of the clear liquid is N-methylpyrrolidone; the antisolvent is isopropyl acetate, methyl tert-butyl ether or toluene; When the crystal form is crystal form VIII of the compound of formula (1), the method is method eight, which includes the following steps: adding the clear liquid containing the compound of formula (1) to the antisolvent and then stirring; the good solvent of the clear liquid is N,N-dimethylformamide; the antisolvent is toluene.

5. The method for preparing the crystal form of the 2,4-disubstituted pyrimidine derivative salt according to claim 4, characterized in that, It satisfies at least one of the following conditions: (1) In the first method, the ambient temperature for gas-solid diffusion is 20-30℃; (2) In Method 1, the gas-solid diffusion time is 6-8 days, for example 7 days; (3) In the first method, after the gas-solid diffusion, drying is performed; the drying time is preferably 2-4 hours, for example 3 hours; the drying temperature is preferably 20-30℃. (4) In the second method, the ratio of the amount of the compound of formula (1) to the amount of the solvent in the suspension is 1g:(10-40)mL; (5) In method two, the stirring temperature is 50°C; (6) In the second method, the stirring time is 3-7 days; (7) In the second method, the solvent is a mixture of isopropanol and water, and the volume ratio of isopropanol to water is (40-50):1, for example 49:

1. In the suspension, the ratio of the amount of the compound of formula (1) to the amount of the solvent is, for example, 1g:(10-20)mL. (8) In the second method, the solvent is 2-methyltetrahydrofuran and water, and the volume ratio of 2-methyltetrahydrofuran to water is (40-50):1, for example 49:

1. In the suspension, the ratio of the amount of the compound of formula (1) to the amount of the solvent is, for example, 1g:(10-20)mL. (9) In the second method, after stirring, the solid is separated and dried; the drying temperature is preferably 20-30℃; the drying time is preferably 2-4h. (10) In the third method, when the good solvent is methanol, the concentration of the compound of formula (1) in the clarified liquid is 50-100 mg / mL; (11) In the third method, when the good solvent is ethanol, the concentration of the compound of formula (1) in the clarified liquid is 5-15 mg / mL; (12) In the third method, when the good solvent is ethanol, the antisolvent is ethyl acetate, isopropyl acetate or methyl tert-butyl ether; (13) In the third method, after the gas-liquid diffusion, drying is carried out; the drying time is preferably 2-4 hours; the drying temperature is preferably 20-30°C. (14) In the fourth method, the ratio of the amount of the compound of formula (1) to the amount of the solvent in the suspension is 1g:(10-40)mL; (15) In method four, the stirring time is 3-7 days; (16) In method four, after stirring, the solid is separated and dried; the drying temperature is preferably 20-30℃; the drying time is preferably 2-4h. (17) In method five, the volume ratio of 2-methyltetrahydrofuran to water is (40-50):1, for example 49:1; (18) In the fifth method, the ratio of the amount of the compound of formula (1) to the amount of the solvent in the suspension is 1g:(10-40)mL; (19) In method five, the stirring time is 3-7 days; (20) In method five, after stirring, the solid is separated and dried; the drying temperature is preferably 20-30℃; the drying time is preferably 2-4h. (21) In method six, the gas-solid diffusion is carried out in an atmosphere with a relative humidity of 92.5%RH; (22) In method six, the gas-solid diffusion time is 6-8 days, for example, 7 days; (23) In method six, after the gas-solid diffusion, drying is performed; the drying time is preferably 2-4 hours, for example 3 hours; the drying temperature is preferably 20-30°C. (24) In the seventh method, the concentration of the compound of formula (1) in the clarified liquid is 50-100 mg / mL; (25) In method seven, the volume ratio of the good solvent to the anti-solvent is 1:(4-10); (26) In the seventh method, the antisolvent is isopropyl acetate, and the volume ratio of the good solvent to the antisolvent is 1:10; (27) In the seventh method, the antisolvent is methyl tert-butyl ether, and the volume ratio of the good solvent to the antisolvent is 1:4; (28) In method seven, the antisolvent is toluene, and the volume ratio of the good solvent to the antisolvent is 1:10; (29) In method seven, the stirring time is 15-20 hours, for example, 18 hours; (30) In method seven, after stirring, the solid is separated and dried; the drying temperature is preferably 20-30℃; the drying time is preferably 2-4h. (31) In method eight, the concentration of the compound of formula (1) in the clarified liquid is 50-100 mg / mL; (32) In method eight, the volume ratio of the good solvent to the anti-solvent is 1:(9-10); (33) In method eight, the stirring time is 15-20 hours, for example, 18 hours; (34) In method eight, after stirring, the solid is separated and dried; the drying temperature is preferably 20-30℃; the drying time is preferably 2-4h. (35) In methods 1 to 8, the compound of formula (1) is crystal form M.

6. A pharmaceutical composition, characterized by, It comprises the crystal form of a 2,4-disubstituted pyrimidine derivative salt as described in any one of claims 1-3; Preferably, the pharmaceutical composition further includes a first filler; the first filler is preferably selected from one or more of microcrystalline cellulose, lactose and pregelatinized starch; the mass ratio of the first filler to the crystal form of the 2,4-disubstituted pyrimidine derivative salt is preferably (25-45):25; Preferably, the pharmaceutical composition further includes a second filler; the second filler is preferably selected from one or more of microcrystalline cellulose, lactose and pregelatinized starch; the mass ratio of the crystal form of the second filler to that of the 2,4-disubstituted pyrimidine derivative salt is preferably (25-45):25; Preferably, the pharmaceutical composition further includes a flow aid; the flow aid is preferably colloidal silica; the mass ratio of the crystal form of the flow aid to that of the 2,4-disubstituted pyrimidine derivative salt is preferably (1-3):25; Preferably, the pharmaceutical composition further includes a disintegrant; the disintegrant is preferably selected from one or more of croscarmellose sodium, croscarmellose, croscarmellose calcium and carboxymethyl starch sodium; the mass ratio of the disintegrant to the crystal form of the 2,4-disubstituted pyrimidine derivative salt is preferably (1-3):25; Preferably, the pharmaceutical composition further includes a lubricant; the lubricant is preferably selected from one or more of magnesium stearate, stearic acid, sodium stearate fumarate, sodium docusate, and calcium stearate; the mass ratio of the lubricant to the crystal form of the 2,4-disubstituted pyrimidine derivative salt is preferably (1-3):

25.

7. The pharmaceutical composition of claim 6, wherein, The dosage form of the pharmaceutical composition is tablets, capsules, powders, granules, ointments, solutions, suspensions, injections, inhalers, gels, microspheres, or aerosols; the injection is preferably an oral preparation or an intravenous injection. Preferably, the pharmaceutical composition comprises the following parts by weight: 25 parts of the crystalline form of the 2,4-disubstituted pyrimidine derivative salt, 25 parts of the first filler, 45 parts of the second filler, 1 part of the lubricant, 1 part of the flow aid, and 3 parts of the disintegrant; the first filler is preferably pregelatinized starch; the second filler is preferably microcrystalline cellulose; the flow aid is preferably colloidal silica; the disintegrant is preferably crospovidone; and the lubricant is preferably magnesium stearate.

8. Use of a crystalline form of a 2,4-disubstituted pyrimidine derivative salt as described in any one of claims 1-3 or a pharmaceutical composition as described in claim 6 in the preparation of a medicament for treating and / or preventing immune diseases, inflammatory-related diseases, or tumors.

9. The use according to claim 8, characterized in that, It satisfies at least one of the following conditions: (1) The tumor is a solid tumor and / or a hematologic malignancy; the solid tumor is preferably lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, ovarian cancer, breast cancer, prostate cancer, bladder cancer, kidney cancer, esophageal cancer, cervical cancer, pancreatic cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, thyroid cancer, brain cancer, lymphoma, epidermal hyperplasia, psoriasis, or prostate cancer; the hematologic malignancy is preferably acute myeloid leukemia, chronic myeloid leukemia, myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, myelodysplastic syndrome, myelodysplastic syndrome, myelofibrosis, multiple myeloma, polycythemia vera, or spinal sarcoma; (2) The immune diseases mentioned are psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, osteoarthritis of the joints, polymyositis, dermatomyositis, periarteritis nodosa, mixed connective tissue disease, scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I and type II diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, Addison's disease, abnormal immune response, arthritis, dermatitis, radiation dermatitis; preferably psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis, or systemic lupus erythematosus; (3) The inflammation-related diseases mentioned are inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome, postoperative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngitis, gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary embolism, sand lung or pulmonary sarcoidosis.

10. The use according to claim 9, characterized in that, It is used to prepare drugs having at least one of the following uses: ①Prepare JAK2 inhibitors or FLT3 inhibitors; ②Treatment and / or prevention of acute myeloid leukemia; ③Treatment and / or prevention of myelodysplastic syndromes; ④ Treatment and / or prevention of myelofibrosis; ⑤ Treatment and / or prevention of essential thrombocytosis; ⑥ Treatment and / or prevention of polycythemia vera; ⑦ Treatment and / or prevention of graft-versus-host disease.

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